Nanozymes for Non-neoplastic Diseases: Catalytic Therapy Redefined

Nanozymes for Non-neoplastic Diseases: Catalytic Therapy Redefined | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Aggregate This is a preprint and has not been peer reviewed. Data may be preliminary. 24 June 2025 V1 Latest version Share on Nanozymes for Non-neoplastic Diseases: Catalytic Therapy Redefined Authors : Ling Mei 0000-0002-2762-2235 , Xikai Wang , Zhuang Hu , Jierui Yan , Xiaobo Wang , Haoran Wang , Ya Hou , Pengfei Zhang 0000-0003-0390-3806 [email protected] , and Qihang Ding 0000-0002-2665-9036 Authors Info & Affiliations https://doi.org/10.22541/au.175072342.22575415/v1 Published Aggregate Version of record Peer review timeline 795 views 357 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Non-neoplastic diseases, such as cardiovascular, neurodegenerative, metabolic, and inflammatory disorders, are major global health challenges with complex pathophysiologies that demand precise and innovative therapeutic strategies. Nanozymes, artificial nanomaterials with enzyme-like catalytic functions, have recently emerged as promising candidates for such interventions. Distinguished by their programmable structures, tunable activities, and excellent biocompatibility, nanozymes can mimic multiple natural enzymes (e.g., superoxide dismutase, catalase, and peroxidase) to modulate oxidative stress and inflammation. Beyond catalytic activity, their functional integration enables immune regulation and metabolic reprogramming, facilitating multi-level (molecular to tissue) microenvironmental remodeling. This review highlights recent progress in nanozyme development for non-neoplastic disease therapy, emphasizing structure–function relationships, activity regulation in pathological conditions, and mechanistic roles in disrupting the oxidative stress–inflammation–immune dysregulation loop. We further summarize representative applications across cardiovascular diseases, neurodegenerative conditions, metabolic disorders, and inflammatory pathologies, focusing on advances in targeted delivery, responsive release, and multimodal theranostics. These insights collectively underline the transformative potential of nanozymes in next-generation precision medicine. Nanozymes for Non-neoplastic Diseases: Catalytic Therapy Redefined 11pt, fleqn, a4paper, ]LegrandOrangeBook Ling Mei, Xikai Wang, Zhuang Hu, Jierui Yan, Xiaobo Wang, Haoran Wang, Ya Hou*, Pengfei Zhang*, Qihang Ding* L. Mei, X. Wang Engineering Research Center for Pharmaceuticals and Equipments of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, China J. Yan, X. Wang Innovative Institute of Chinese Medicine and Pharmacy/Academy for Interdiscipline, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China Z. Hu Ningbo Municipal Hospital of Traditional Chinese Medicine, Affiliated Hospital of Zhejiang Chinese Medical University, Ningbo 315000, China H. Wang Faculty of Materials Science, Shenzhen MSU-BIT University, Shenzhen, 518115, China. Y. Hou TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, Sichuan, China. Email: [email protected] P. Zhang Guangdong Key Laboratory of Nanomedicine, Chinese Academy of Sciences-Hong Kong Joint Lab for Biomaterials, Chinese Academy of Sciences Key Laboratory of Biomedical Imaging Science and System, Center for Nanomedicine and Nanobiotechnology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. Email: [email protected] Q. Ding Department of Chemistry, Korea University, Seoul 02841, Korea Email: [email protected] Abstract ： Non-neoplastic diseases, such as cardiovascular, neurodegenerative, metabolic, and inflammatory disorders, are major global health challenges with complex pathophysiologies that demand precise and innovative therapeutic strategies. Nanozymes, artificial nanomaterials with enzyme-like catalytic functions, have recently emerged as promising candidates for such interventions. Distinguished by their programmable structures, tunable activities, and excellent biocompatibility, nanozymes can mimic multiple natural enzymes (e.g., superoxide dismutase, catalase, and peroxidase) to modulate oxidative stress and inflammation. Beyond catalytic activity, their functional integration enables immune regulation and metabolic reprogramming, facilitating multi-level (molecular to tissue) microenvironmental remodeling. This review highlights recent progress in nanozyme development for non-neoplastic disease therapy, emphasizing structure–function relationships, activity regulation in pathological conditions, and mechanistic roles in disrupting the oxidative stress–inflammation–immune dysregulation loop. We further summarize representative applications across cardiovascular diseases, neurodegenerative conditions, metabolic disorders, and inflammatory pathologies, focusing on advances in targeted delivery, responsive release, and multimodal theranostics. These insights collectively underline the transformative potential of nanozymes in next-generation precision medicine. Keywords: Non-neoplastic diseases, Nanozymes, Theranostics, Reactive oxygen species, Inflammation 11pt, fleqn, a4paper, ]LegrandOrangeBook 1. Introduction Non-neoplastic diseases, including cardiovascular, neurodegenerative, metabolic, and inflammatory disorders[1], pose persistent global health burdens due to their complex etiologies, multifactorial progression, and limited responsiveness to conventional therapies. Central to many of these pathologies is the disruption of redox homeostasis, chronic inflammation, and immune dysregulation, forming a vicious cycle that drives tissue damage and impedes recovery[2, 3]. Accordingly, there is a growing demand for therapeutic platforms that integrate multi-targeted, responsive, and biocompatible strategies capable of intervening in these intertwined pathological circuits. Nanozymes, artificial nanomaterials endowed with enzyme-mimicking catalytic activities, have recently emerged as versatile candidates for next-generation precision medicine[4-6]. Unlike natural enzymes, nanozymes possess superior stability, tunable reactivity, and structural adaptability, enabling them to operate effectively under pathological conditions characterized by oxidative stress, acidic pH, or high ROS burden[7]. By recapitulating the functions of superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD)[8], nanozymes offer powerful means of scavenging excessive reactive oxygen/nitrogen species (ROS/RNS), reshaping inflammatory microenvironments, and restoring immune-metabolic balance. Beyond their catalytic roles, recent advances in nanozyme engineering have introduced platforms capable of intelligent delivery, microenvironment-triggered activation, and synergistic therapeutic integration[9-11]. These systems not only enhance therapeutic precision but also allow dynamic modulation of immune responses and metabolic pathways, facilitating tissue repair and regeneration[12-14]. Notably, the intersection of nanocatalysis with immunoengineering and metabolic intervention is driving a paradigm shift in the treatment of non-neoplastic diseases—from symptom alleviation toward disease modification[15]. In this review, we systematically summarize recent advances in the design, mechanism, and therapeutic application of nanozymes for non-neoplastic diseases. We first elucidate the classification and catalytic mechanisms of representative nanozymes, focusing on their redox regulation under pathophysiological conditions. We then highlight their roles in mitigating oxidative stress, modulating inflammation, and reprogramming immune responses across major disease contexts, including atherosclerosis (AS), myocardial infarction (MI), neurodegenerative diseases (e.g., Alzheimer’s and Parkinson’s), metabolic disorders (e.g., diabetes and insulin resistance), and immune-related pathologies. Special attention is given to structure–function correlations, disease-specific delivery strategies, and intelligent platforms that enable spatiotemporally controlled interventions. Finally, we discuss existing challenges and future opportunities for the clinical translation of nanozyme-based therapeutics ( Scheme 1 ). Together, these insights establish nanozymes as powerful tools in the expanding arsenal of nanomedicine, capable of addressing the multifaceted complexity of non-neoplastic diseases through systems-level intervention and catalytic precision. Scheme 1 Schematic diagram of the therapeutic mechanism of nanozymes. Created in https://BioRender.com. 2. Classes and Catalytic Mechanisms of Nanozymes 2.1 Classification of Nanozymes Nanozymes, nanomaterials with intrinsic enzyme-mimicking catalytic activities, are increasingly recognized as promising candidates for the treatment of inflammatory diseases owing to their unique catalytic versatility, favourable biocompatibility, and high engineering adaptability[16, 17]. In particular, in inflammation driven by oxidative stress, nanozymes can precisely regulate intracellular and extracellular ROS levels, thereby attenuating tissue damage and orchestrating immune microenvironment remodelling[18]. Metal oxide nanozymes, such as Fe 3 O 4 and MnO 2 , have been extensively explored for their POD - or oxidase (OXD)-like activities, offering efficient ROS scavenging while dampening pro-inflammatory responses. Fe 3 O 4 nanozymes catalyse the decomposition of endogenous hydrogen peroxide (H 2 O 2 ) into water and oxygen[19], simultaneously mitigating oxidative stress and achieving magnetic field-guided accumulation at inflamed sites to suppress the release of inflammatory mediators[20]. MnO 2 nanozymes further exhibit acid-responsive catalytic activity, decomposing H 2 O 2 and superoxide anions (O 2 •⁻ ) within acidic inflammatory microenvironments to relieve local hypoxia and inhibit NF-κB signalling. Moreover, the facile surface functionalization of MnO 2 provides a versatile platform for constructing multifunctional anti-inflammatory nanotherapeutics[21]. Carbon-based nanozymes, including graphene derivatives and carbon nanotubes, also offer distinct advantages owing to their dual OXD-like and antioxidant enzyme-like activities[22]. Their large surface area enables efficient adsorption of inflammatory mediators and simultaneous delivery of therapeutic cargos[23], thereby promoting synergistic therapeutic outcomes. Graphene oxide, for instance, exerts SOD-like activity to eliminate ROS and polarizes macrophages towards the anti-inflammatory M2 phenotype, promoting inflammation resolution[24, 25]. Nitrogen-doped carbon nanotubes can further catalyse nitric oxide (NO) production, thereby enhancing vasodilation, suppressing platelet aggregation, and improving local tissue perfusion. Importantly, their excellent electrical conductivity and chemical stability make them highly attractive for the management of chronic inflammatory conditions. Precious metal-based nanozymes and metal–organic framework (MOF)-derived nanozymes further broaden the functional landscape. Gold nanoparticles (Au NPs), with CAT-like activity, help maintain mitochondrial redox homeostasis, and their surface plasmon resonance (SPR) effects enable integration with photothermal anti-inflammatory strategies[7, 26, 27]. Platinum (Pt) -based nanozymes have shown superior ROS scavenging performance in systemic inflammatory models such as sepsis[28], effectively reducing oxidative damage. MOF-based nanozymes, exemplified by Fe-MIL-101, combine robust POD-like activity with intrinsic porosity for high-efficiency drug encapsulation and inflammation-responsive release, thereby enhancing therapeutic efficacy while minimizing off-target toxicity[29] ( Table 1 ). Overall, nanozymes exhibit remarkable catalytic diversity and structural tunability, offering unique advantages for the treatment of inflammatory diseases. Through distinct catalytic mechanisms, ranging from ROS scavenging and immune modulation to microenvironmental remodeling, various classes of nanozymes, including metal oxides, carbon-based materials, precious metals, and MOF-derived structures, have demonstrated potent anti-inflammatory potential. Their versatile surface chemistry further enables multifunctional integration, positioning nanozymes as highly promising candidates for precise and personalized anti-inflammatory therapies. Table 1 Classification, Catalytic Activity, and Therapeutic Mechanisms of Nanozymes in Disease Treatment math_shortcuts Metal Oxides Fe₃O₄ CAT, POD Atherosclerosis, Rheumatoid Arthritis Scavenging excess ROS, inhibiting inflammatory responses [19, 20] MnO₂ SOD, CAT Ischemic Diseases Scavenging ROS, alleviating oxidative stress and inflammatory damage [21] CeO₂ SOD, CAT Parkinson’s Disease Scavenging ROS, protecting cells from oxidative damage [30] Mn₃O₄ SOD Parkinson’s Disease Scavenging superoxide anion radicals, mitigating neuroinflammation [31] Cu₂₋ₓSe-TPP SOD, CAT Alzheimer’s Disease Mitochondria-targeted ROS scavenging, protecting neurons [32] Cu-TCPP-Mn SOD, CAT Myocardial Infarction Scavenging ROS, promoting myocardial repair [33] Cu-rhein NSs SOD Diabetic Wounds Scavenging ROS, promoting wound healing [34] CA-Mn NPs CAT, SOD Fatty Liver Disease Scavenging ROS and regulating metabolism, improving liver function [35] CoO SOD, CAT, POD Atopic Dermatitis Synergistic multi-enzyme activity for ROS scavenging, inhibiting inflammation [36] Carbon-Based Materials GO SOD, POD Chronic Inflammation Adsorbing inflammatory mediators and catalyzing ROS decomposition, exerting anti-inflammatory effects [22] N-CNT SOD, NO Synthase Cardiovascular Diseases Synthesizing NO and scavenging ROS, vasodilation, inhibiting platelet aggregation [24] Zn/C-dots SOD, CAT, GPx Diabetic Wounds Multi-enzyme ROS scavenging, antibacterial activity, promoting tissue repair [37] Noble Metals Au CAT, GOD Skin Inflammation, Diabetic Retinopathy Scavenging ROS and regulating metabolism, protecting tissue [7, 26] Pt SOD, CAT, POD Inflammatory Diseases Synergistic multi-enzyme activity for ROS scavenging, attenuating oxidative stress [28] PdH CAT Atherosclerosis Decomposing H₂O₂, alleviating oxidative stress and inflammation [38] Ru³⁺-NMOFs POD Alzheimer’s Disease Catalyzing H₂O₂ to generate ·OH, disrupting Aβ fibrils and alleviating neuroinflammation [39] PtCuSe SOD, CAT Parkinson’s Disease Efficient ROS scavenging, protecting neurons [40] Pd–Pt MXene POD Alzheimer’s Disease Catalyzing ·OH generation for Aβ disaggregation and neuroinflammation regulation [41] Metal-Organic Frameworks Fe-MIL-101 POD Inflammatory Bowel Disease Targeted drug delivery and responsive release in the inflammatory microenvironment, enhancing efficacy [29] ZIF-8 SOD Acute Pancreatitis, Myocardial Repair Scavenging ROS, modulating inflammation, promoting tissue regeneration [42, 43] Zr-FeP MOF POD Parkinson’s Disease Depleting ROS substrate required for inflammasome activation [44] PCN222-Mn SOD, CAT Inflammatory Bowel Disease Scavenging ROS, modulating gut immune microenvironment [45] Neu-MOF/Fla Hydrolase Alzheimer’s Disease Hydrolyzing pro-inflammatory mediators, remodeling neuroinflammatory microenvironment [46] Fe-Cur@TA CAT Myocardial Infarction Scavenging ROS, synergistically inhibiting inflammation and promoting myocardial repair [47] 2.2 Catalytic Activities of Nanozymes By mimicking the catalytic activities of natural enzymes, nanozymes have demonstrated broad application potential in the treatment of non-neoplastic diseases[48]. Among them, nanozymes exhibiting CAT-like, SOD-like, and POD-like activities play pivotal roles in regulating oxidative stress and modulating immune-inflammatory responses[49, 50]. Fundamentally, these enzymatic activities rely on redox reactions mediated by variable-valence metal centers or defect sites on the surface of nanomaterials, which facilitate electron transfer and enable precise control over ROS levels[51] ( Scheme 2 ). 2.2.1 CAT-Like Activity of Nanozymes CAT-like nanozymes catalyze the disproportionation of H 2 O 2 into water and oxygen, thereby mitigating oxidative stress within cells. Their catalytic centers typically depend on the redox cycling of transition metal ions such as Fe, Mn, Ce, or Co, which mediate efficient electron transfer during catalysis[52, 53]. For instance, Bing and colleagues systematically investigated CAT-like activity exhibited by ferric oxide (Fe₃O₄) nanoparticles (NPs) in the treatment of ischemic stroke models[54]. The study demonstrated that this Fe₃O₄ nanozyme significantly reduced cerebral infarct volume and neuronal death in rodent models of cerebral ischemic stroke. In another study, Lei et al. [55]developed Pt-based nanozymes that suppress macrophage inflammatory polarization via ROS scavenging, thereby ameliorating inflammation in RA. Furthermore, this nanozyme also ameliorated the hypoxic environment and inhibited angiogenesis and bone destruction, demonstrating promising therapeutic efficacy against RA. Collectively, CAT-like nanozymes exhibit marked advantages in scavenging toxic H 2 O 2 , making them particularly suitable for treating oxidative stress-driven chronic inflammatory diseases such as cardiovascular diseases, RA, neurodegenerative disorders (pending solutions for blood-brain barrier (BBB) penetration), and ischemia-reperfusion injuries[28]. 2.2.2 SOD-Like Activity of Nanozymes SOD-like nanozymes catalyze the disproportionation of O 2 •⁻ into H 2 O 2 and O 2 (2O 2 •⁻ + 2H⁺ → H 2 O 2 + O 2 ), constituting the first line of defense in ROS scavenging systems. Their catalytic activity typically depends on variable-valence states of Mn, Cu, or Ce ions, or on defect structures such as oxygen vacancies that facilitate single-electron transfer reactions[56, 57]. For example, the group led by Lee designed cerium oxide (CeO 2 ) NPs exhibiting dual SOD- and CAT-like activities for the intervention of acute kidney injury (AKI)[30]. These nanozymes leveraged Ce 3+ /Ce 4+ redox cycling and abundant oxygen vacancies to efficiently eliminate O 2 •⁻ , while simultaneously catalyzing the conversion of H 2 O 2 , thereby establishing a cascade antioxidant defense system. This dual action effectively attenuated tubular cell damage and inflammatory responses, promoting renal functional recovery. Similarly, Hyeon and colleagues developed manganese-based nanozymes (e.g., Mn 3 O 4 ) that displayed robust SOD-like activity in models of Parkinson’s disease (PD)[31]. These nanozymes were capable of traversing the BBB and selectively scavenging O 2 •⁻ generated by dopaminergic neurons in the substantia nigra, thereby alleviating oxidative neuronal damage and neuroinflammation to delay neurodegeneration. Overall, SOD-like nanozymes are particularly valuable for diseases characterized by O 2 •⁻ accumulation. Given that H 2 O 2 is generated as a byproduct, combining SOD-like activity with CAT-like functionality is often necessary to establish a closed-loop antioxidant defense system. 11pt, fleqn, a4paper, ]LegrandOrangeBook 2.2.3 POD-Like Activity of Nanozymes POD-like nanozymes catalyze the activation of H 2 O 2 to generate highly reactive hydroxyl radicals (·OH) or other oxidative species, driving the oxidation of substrate molecules (e.g., H 2 O 2 + o-phenylenediamine → 2H 2 O + oxidized product). This process generally relies on high-valence catalytic centers of Fe or Mn, which produce reactive intermediates such as ·OH or metal-oxo species[58, 59]. Chen and co-workers constructed FeS 2 nanozymes exhibiting remarkable POD-like activity for treating IBD[60]. These nanozymes selectively activated H 2 O 2 within the slightly acidic microenvironment of the inflamed intestine, generating ·OH in situ to eradicate pathogenic microorganisms, remodel the gut microbiota, alleviate inflammatory responses, and facilitate mucosal repair. Additionally, Wei and colleagues developed vanadium-based nanozymes with combined POD and glutathione peroxidase (GPx)-like activities for treating diabetic chronic wound infections[61]. In hyperglycemic environments characterized by excessive H 2 O 2 and severe infections, these nanozymes catalyzed the generation of ·OH to rapidly eradicate multidrug-resistant bacteria. Simultaneously, the GPx-like activity modulated local redox homeostasis, thereby promoting angiogenesis and tissue regeneration. POD-like nanozymes offer a ”fighting fire with fire” strategy, transforming pathological H 2 O 2 into cytotoxic ROS for antimicrobial or pro-apoptotic purposes. Such approaches are particularly suited for infectious inflammatory diseases (e.g., skin ulcers, IBD with infection, bacterial pneumonia) and targeted elimination of pathogenic cells (e.g., psoriasis). The major challenge, however, lies in balancing efficacy with biosafety, necessitating precise delivery strategies or disease microenvironment-responsive mechanisms (e.g., acidic pH, elevated H 2 O 2 concentrations) for clinical translation. Scheme 2 Schematic diagram of the classification and catalytic mechanisms of nanozymes. Created in https://BioRender.com. 3. Therapeutic Mechanisms of Nanozymes in Non-neoplastic Diseases 3.1 Antioxidant Activity Oxidative stress plays a pivotal role in the onset and progression of various non-neoplastic diseases. Owing to their biomimetic catalytic activities resembling those of natural antioxidant enzymes, including SOD, CAT, and POD, nanozymes have emerged as a promising strategy for modulating redox homeostasis and mitigating oxidative stress-related pathological damage[62, 63]. By precisely regulating the levels of ROS and RNS, nanozymes not only directly scavenge free radicals to alleviate oxidative toxicity but also enhance antioxidant capacity through structural engineering and immune modulation, thereby contributing to anti-inflammatory effects, tissue protection, and functional repair[64, 65]. Fundamentally, nanozymes can efficiently catalyse the conversion of ROS and RNS, transforming highly toxic free radicals, including O 2 •⁻ , H 2 O 2 , ·OH, and peroxynitrite (ONOO⁻), into less harmful or inert species such as water and oxygen, thereby markedly reducing the accumulation of oxidative molecules in inflamed microenvironments[66]. For example, Pt-based nanozymes and ultrasmall Cu 5.4 O nanozymes have demonstrated potent radical scavenging capacities, effectively mitigating oxidative tissue damage[67, 68]. Jiang and colleagues developed Pt nanozymes exhibiting dual SOD- and CAT-like catalytic activities, where O 2 •⁻ is first converted to H 2 O 2 (SOD-mimetic activity), followed by decomposition into O 2 and H 2 O (CAT-mimetic activity). This cascade reaction efficiently eliminates ROS, ·OH, and ONOO⁻ within neurons, significantly suppressing α-synuclein aggregation and NF-κB pathway activation, ultimately protecting dopaminergic neurons in PD models[69]. Importantly, the antioxidant properties of nanozymes are closely correlated with their structural attributes. By tailoring parameters such as particle size, morphology, and surface chemistry (e.g., ligand functionalisation, charge modulation), nanozymes can achieve enhanced accumulation at diseased sites and improved catalytic selectivity[70]. Liu et al. designed Janus-type Fe 3 O 4 -MnO 2 nanozymes featuring asymmetric architectures that spatially separate functional modules for synergistic catalysis[71]. the Fe 3 O 4 domain possesses POD-like activity, catalysing H 2 O 2 into ·OH in the acidic microenvironment of inflamed tissues to exert antibacterial effects, while the MnO 2 domain exhibits CAT-like activity, decomposing H 2 O 2 into O 2 in normal tissues to alleviate local hypoxia and restrain excessive oxidative reactions. This structure-function-integrated design provides a versatile approach for the precise treatment of oxidative stress-related disorders. Beyond direct radical scavenging, nanozymes can systemically regulate immune-inflammatory responses by modulating redox signalling pathways. For instance, Wei et al. [72]developed porous CeO 2 nanozymes that exhibited robust antioxidant and immunomodulatory activities in chronic obstructive pulmonary disease (COPD) models. The nanozyme leveraged the reversible Ce 3+ /Ce 4+ redox cycling and abundant surface oxygen vacancies to sustain SOD- and CAT-like activities, effectively eliminating O 2 •⁻ and H 2 O 2 induced by cigarette smoke exposure. Concurrently, it inhibited the activation of NLRP3 inflammasomes and the expression of IL-1β and IL-18, while downregulating NF-κB and MAPK pathways. Additionally, the CeO 2 nanozyme activated the Nrf2 antioxidant pathway, thereby enhancing the expression of endogenous antioxidant enzymes, including HO-1 and GPx, to establish a coordinated intracellular and extracellular antioxidant defence system. Collectively, nanozymes, by integrating biomimetic catalytic functions, structure-engineered modulation, and immune microenvironment intervention, hold significant promise for antioxidant therapies in non-neoplastic diseases. Future efforts should prioritise improving tissue-specific targeting, catalytic selectivity, and biosafety to facilitate clinical translation in the treatment of chronic inflammation, neurodegenerative disorders, and metabolic diseases. 3.2 Anti-Inflammatory Activity The role of nanozymes in inflammation regulation has garnered increasing attention, with their anti-inflammatory mechanisms operating synergistically across three principal levels: signaling pathway modulation, direct inhibition of inflammatory mediators, and cytoprotective effects. These mechanisms collectively establish a systemic anti-inflammatory network[73]. Primarily, nanozymes mitigate excessive ROS, disrupting the positive feedback loop between oxidative stress and inflammatory activation, thereby suppressing key pro-inflammatory signaling cascades, most notably the NF-κB and MAPK pathways[74]. For instance, Fe 3 O 4 nanozymes inhibit phosphorylation of the IκB kinase (IKK) complex, preventing IκBα degradation and NF-κB nuclear translocation, leading to marked downregulation of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. In RA models, Fe 3 O 4 nanozymes developed by Farokhzad et al. leverage their POD-like activity to reduce intra-articular H 2 O 2 levels, thereby alleviating inflammatory burden at the source. Concurrently, these nanozymes inhibit phosphorylation of JNK and p38 MAPK, resulting in a 60–80% decrease in secretion of inflammatory mediators. Secondly, nanozymes directly interfere with phosphorylation of MAPK components—JNK and p38—attenuating downstream signaling and consequently reducing the synthesis and release of pro-inflammatory cytokines[75, 76]. Moreover, nanozymes suppress production of inflammatory mediators such as NO, TNF-α, and IL-6, weakening immune cell chemotaxis and diminishing cytokine gradients within the inflammatory microenvironment[76]. Critically, the ROS scavenging ability of nanozymes extends beyond signal inhibition to molecular-level protection of cellular membranes, proteins, and DNA, preventing ROS-induced apoptosis and necrosis, thus preserving tissue microenvironment homeostasis[77]. CeO 2 nanozymes scavenge diverse ROS, suppress the MAPK and NF-κB signaling pathways, and reduce pro-inflammatory mediators[78]. Meanwhile, Mn₃O₄ nanozymes demonstrate considerable potential for treating and preventing ROS-mediated neuroinflammation owing to their exceptional ROS scavenging capabilities[79]. Additionally, Pt-Se hybrid nanozymes exhibit potent anti-inflammatory and chondroprotective effects. By scavenging ROS and suppressing the expression of inflammatory mediators, they offer a novel therapeutic strategy for inflammation-associated diseases[80].Nanozymes orchestrate multi-dimensional intervention in inflammatory processes, modulating pro-inflammatory pathways at the signaling level while exerting critical control over effector molecules and cellular homeostasis, thus offering novel and systemic therapeutic strategies for inflammation-related diseases. math_shortcuts 3.3 Immunomodulatory Effects Nanozymes are increasingly recognized for their unique, multi-faceted immunomodulatory capabilities in treating non-neoplastic diseases[81, 82]. Through targeted delivery, metabolic intervention, and signal pathway reprogramming, nanozymes affect systemic immune remodeling at molecular, cellular, and tissue scales, principally manifested in three aspects: Firstly, in immune cell phenotype regulation, nanozymes achieve precise targeting and intervention via surface functionalization. Sulfur quantum dot-based nanozymes, which mimic the cascade catalysis of SOD and CAT, efficiently scavenge ROS at disease sites, ameliorating local oxidative stress. In osteomyelitis models, these nanozymes suppressed pro-inflammatory pathways such as HIF-1α and NF-κB in osteoclasts, while markedly inducing macrophage polarization from pro-inflammatory M1 (CD86⁺) to anti-inflammatory M2 (CD206⁺) phenotype, with polarization rates exceeding 65%. This shift was accompanied by downregulation of TNF-α and IL-6, alongside upregulation of the anti-inflammatory cytokine IL-10, thereby accelerating repair of infectious bone defects[83]. Secondly, in immune homeostasis restoration, nanozymes precisely modulate immune cell function through metabolic pathways. For example, an arginine metabolism-responsive nanozyme developed by He et al.[84]regulates NO production and the ornithine pathway, simultaneously promoting angiogenesis and collagen synthesis, while suppressing overactivation of Th17 cells and enhancing the immunosuppressive function of regulatory T cells (Tregs). This mechanism exhibits therapeutic potential in chronic inflammatory diseases such as AS, highlighting nanozymes’ promise in T cell metabolic regulation and immune homeostasis recovery[85, 86]. Lastly, regarding synergistic modulation of signaling pathways and tissue repair promotion, nanozymes, by virtue of their multifunctional coupling properties, co-deliver reparative factors such as vascular endothelial growth factor (VEGF) while selectively inhibiting innate immune pathways, including cGAS, STING, to dampen inflammatory cascades[87]. These approaches not only suppress inflammatory mediator production but also directly stimulate the proliferation and migration of fibroblasts and vascular endothelial cells, achieving spatiotemporal coordination of inflammation resolution and tissue regeneration. Their multi-targeted and dynamically responsive features hold great promise for precise and systemic interventions in immune dysregulation-related diseases[88] ( Scheme 3 ). Nanozymes construct an integrated therapeutic network encompassing antioxidant defense, anti-inflammatory response, and tissue repair by regulating immune cell phenotypes, reconstructing immune metabolic balance, and modulating immune signaling pathways. Compared to conventional single-target therapeutics, nanozymes offer novel strategies and theoretical foundations for immunotherapy of complex non-neoplastic diseases, demonstrating broad clinical translation potential. 11pt, fleqn, a4paper, ]LegrandOrangeBook Scheme 3 Schematic diagram of nanozymes for the treatment of non-neoplastic diseases. Created in https://BioRender.com. math_shortcuts 4. Nanozyme Applications in Non-neoplastic Diseases 4.1 Cardiovascular Diseases 4.1.1 Nanozyme-Based Therapeutics in Atherosclerosis AS is a prototypical chronic and progressive cardiovascular disease, pathologically characterized by endothelial dysfunction, dysregulated lipid metabolism, and persistent inflammatory activation. These factors interact to form a vicious cycle that drives disease progression. Upon endothelial barrier disruption, low-density lipoprotein (LDL) readily accumulates in the intima and undergoes oxidation to form ox-LDL, which is subsequently internalized by macrophages to generate foam cells, triggering chronic inflammation and plaque formation. Sustained oxidative stress and immune activation exacerbate vascular injury and lesion advancement. Therefore, the development of precision interventions targeting multiple pathological mechanisms and breaking this pathological cascade is of critical scientific importance. In recent years, synthetic nanozymes, nanomaterials with enzyme-mimicking catalytic activities, have emerged as promising tools for modulating the pathological microenvironment of AS, owing to their tunable physicochemical properties, catalytic versatility, and favorable biocompatibility. Through rational design, nanozymes can mimic antioxidant enzymes to scavenge ROS while enabling targeted delivery at the cellular subpopulation level via surface modification. Additionally, their integration of diagnostic and therapeutic functionalities offers novel strategies for multidimensional precision intervention in AS. Targeted delivery is a prerequisite for therapeutic efficacy. Chen et al.[89] developed pep-CDs nanozymes modified with CLIKKPF peptides, which selectively bind to phosphatidylserine exposed on foam cell membranes, enabling specific localization to atherosclerotic plaques. Similar approaches include Lv’s Cur/MOF@DS [90]and Li’s HCN@DS nanozymes[91], which utilize dextran sulfate (DS) to target macrophages and foam cells within plaques. Wang et al. [92]functionalized CS-Lip/PB@Rap with chondroitin sulfate (CS), enabling dual recognition of inflammatory macrophages and vascular smooth muscle cells (VSMCs). In another example, HA-CeO 2 nanozymes leveraged hyaluronic acid (HA) to target CD44 receptors on macrophages, achieving efficient plaque-specific accumulation[93]. Once localized, nanozymes efficiently eliminate ROS, disrupting the oxidative stress-inflammation feedback loop central to AS progression. He et al. [94]reported PBNZ@PP-Man, a Prussian blue (PB)-based nanozyme with SOD- and CAT-like activities that markedly reduces ROS levels in plaques. PdH nanozymes ( Figure 1A ), with a unique tetrapod morphology as described by Hu et al.,[38] demonstrated strong intracellular antioxidative capabilities in macrophages. Other systems, including Cur/MOF@DS[90], CS-Lip/PB@Rap[92], and HA-CeO 2 NPs[93], have also been validated for their ability to scavenge peroxyl radicals and H 2 O 2 , alleviating oxidative stress-induced cellular dysfunction and inflammation. By mitigating oxidative stress, nanozymes concurrently modulate inflammatory responses and suppress immune activation within lesions. PBNZ@PP-Man, modified with P-selectin ligand and mannose, targets both endothelial cells and macrophages, reducing leukocyte recruitment and inflammatory cytokine secretion, thereby interrupting early plaque formation[94]. CS-Lip/PB@Rap further disrupts pro-inflammatory feedback between macrophages and VSMCs, effectively suppressing chronic inflammation within lesions[92]. Beyond antioxidation and anti-inflammation, nanozymes can reprogram macrophage functionality to promote plaque stabilization and regression. The tetrapod-shaped PdH nanozyme induces autophagy in macrophages, facilitating the degradation of damaged organelles and lipid droplets to maintain cellular homeostasis. Cur/MOF@DS and CS-Lip/PB@Rap have also been shown to induce autophagy and drive macrophage polarization toward the anti-inflammatory M2 phenotype[90, 92]. Notably, Li’s HCN@DS system employs photoacoustic and photothermal imaging-guided localized mild photothermal therapy to trigger autophagy and promote cholesterol efflux, thereby reducing foam cell formation and directly reversing intraplaque lipid accumulation[91]. Moreover, certain nanozymes impede lipid uptake to further arrest disease progression. HA-CeO 2 nanozymes suppress ox-LDL phagocytosis by macrophages while maintaining antioxidative activity, preventing the formation of new foam cells (Figure 1B ). Similarly, HCN@DS nanozymes demonstrate inhibitory effects on lipid uptake, enhancing their regulatory influence on lipid metabolism[91, 93]. Importantly, several nanozymes incorporate diagnostic functionalities, facilitating image-guided therapy. pep-CDs possess inherent deep-red fluorescence emission and photoacoustic responsiveness, enabling real-time visualization of plaques. Cur/MOF@DS and HCN@DS exhibit excellent magnetic resonance imaging and photoacoustic/photothermal imaging (PAI/PTI) capabilities, respectively, supporting early diagnosis, treatment monitoring, and personalized therapy in AS[89-91]. Nanozymes orchestrate a comprehensive therapeutic paradigm for AS via five synergistic mechanisms: targeted delivery, ROS scavenging, inflammation modulation, functional reprogramming, and theranostic integration. By systematically remodeling the local microenvironment, nanozymes effectively interrupt AS pathogenesis and show substantial promise in cardiovascular therapy. Looking forward, intelligent nanozyme platforms featuring stimulus-responsiveness, controlled release, and multimodal imaging may accelerate clinical translation, ushering in a new era of precision cardiovascular medicine. 4.1.2 Nanozyme-Mediated Modulation of Post-MI Inflammation Although the inflammatory response following MI is an intrinsic repair mechanism initiated by the body, excessive or prolonged inflammation can lead to secondary myocardial damage, adverse ventricular remodeling, and progressive cardiac dysfunction. Therefore, precise intervention targeting the oxidative stress–inflammation cascade has become a critical strategy in post-MI therapeutic management. In recent years, nanozymes—nanomaterials with tunable multi-enzyme-like catalytic activities, robust antioxidative performance, and favorable tissue affinity—have emerged as cutting-edge tools for modulating the post-MI inflammatory microenvironment. They exhibit multidimensional regulatory capabilities, including the elimination of excessive ROS, inhibition of pro-inflammatory signaling pathways, immune cell phenotype reprogramming, and promotion of cardiomyocyte survival, thereby disrupting the vicious cycle of ROS and inflammation and reshaping the cardiac repair microenvironment. In terms of oxidative stress regulation, nanozymes can simulate natural antioxidant enzymes, such as SOD and CAT, to catalyze cascade reactions that efficiently remove ROS accumulated in infarcted tissues. Xiang and colleagues developed a bimetallic nanozyme, Cu-TCPP-Mn[33], constructed using an MOF scaffold that synergistically modulates Cu and Mn active centers. This design enables effective dismutation of O 2 •⁻ and subsequent decomposition of H 2 O 2 , ultimately generating harmless H 2 O and O 2 . This system achieved a ROS clearance rate of up to 92%. The biomimetic antioxidative mechanism of Cu-TCPP-Mn significantly alleviated local myocardial oxidative damage, laying a stable foundation for downstream immune modulation. Beyond ROS scavenging, nanozymes play an essential role in modulating inflammatory signaling and immune cell infiltration. These nanoplatforms inhibit the expression of chemokines and reshape macrophage functionality, thereby mitigating local hyperinflammatory responses. Cu-TCPP-Mn not only eliminates ROS but also significantly downregulates monocyte chemoattractant protein-1 expression, reducing monocyte infiltration into the infarcted region by 68%. [33]Simultaneously, it enhances macrophage phagocytosis of necrotic cardiomyocytes, accelerating inflammation resolution and tissue clearance. Another representative system, Fe-Cur@TA, developed by Liu’s group[47], employs a synergistic triple mechanism for anti-inflammation: the Fe 3+ core catalyzes ROS decomposition, curcumin inhibits key pro-inflammatory pathways such as NF-κB, and tannic acid (TA) modification enhances targeting and immunosuppressive activity ( Figure 1C ). This system effectively suppresses inflammatory cytokine release and immune cell infiltration, ultimately reducing fibrotic scar formation. Nanozymes also demonstrate powerful regulatory potential in macrophage phenotype reprogramming. Zhong et al. [95]designed an ALG-(ZIF-8) hydrogel system as a “microenvironment-responsive” platform for controlled release. The alginate-based hydrogel forms a stable local delivery matrix, enabling sustained release of ZIF-8 nanozymes in the infarcted area and maintaining consistent SOD/CAT activity. This leads to a 58% reduction in TNF-α expression and promotes the M1-to-M2 phenotypic transition in macrophages ( Figure 1D ). Additionally, Zn 2+ released from ZIF-8 significantly enhances neovascularization, increasing vascular density by 2.1-fold and restoring cardiac function to 82% of baseline. Further advancing this concept, Chen’s team [96]engineered a ZIF-8zyme system with structural responsiveness to inflammatory microenvironments. Under acidic pH and elevated ROS conditions, the MOF structure undergoes accelerated degradation, resulting in a 3.5-fold increase in Zn 2+ release. This enhances M2 polarization efficiency by 2.8-fold compared to controls, suppresses pro-inflammatory cytokines such as IL-6 by 74%, and improves cardiomyocyte survival from 41% to 83%. Overall, nanozymes exhibit unprecedented therapeutic potential in modulating post-MI inflammation, owing to their multidimensional catalytic properties, responsive release mechanisms, and precise control over immune cell phenotypes. Driven by advances in metal coordination chemistry, carrier engineering, and pathological microenvironment sensing, nanozymes are propelling cardiovascular therapy toward intelligent and precision-based interventions. These systems represent a transformative paradigm for inflammation regulation in MI and beyond. Figure 1 ( A ). Schematic of the synthesis of TN-PdH@Ms and its autophagy - synergetic multiple effects for treating AS[38]. Copyright 2022 American Chemical Society. ( B ). Schematic of surface-bound HA generating ceria nanozymes to better ease AS[93].Copyright 2022 Elsevier Ltd. ( C ). Schematic of preparing drug - based nanozyme (Fe-Cur@TA) and using it to treat MI by cardiac-targeted blocking of the excessive inflammation - free radicals vicious cycle[47]. Copyright 2023 Wiley-VCH GmbH. ( D ). ALG-(ZIF-8), a zinc-based nanozyme injectable multifunctional hydrogel for MI treatment. ZIF-8 is mainly prepared by mixing zinc nitrate and 2-methylimidazole in a hydrothermal system. Zinc ions from ZIF-8 help cross-link sodium alginate, forming injectable composite hydrogel ALG-(ZIF-8). With SOD-like and CAT-like activity, ALG-(ZIF-8) scavenges ROS. Also, released zinc ions enhance biological activity and synergistically boost post - myocardial - infarction cardiac - function recovery[95]. Copyright 2024 Acta Materialia Inc. 4.2 Neurodegenerative Diseases 11pt, fleqn, a4paper, ]LegrandOrangeBook 4.2.1 Nanozyme-Based Therapy for Alzheimer’s Disease (AD) AD, a progressive neurodegenerative disorder characterized by cognitive decline, is pathologically marked by extracellular amyloid-β (Aβ) plaque accumulation, intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, and extensive neuronal loss. In recent years, nanozymes—nanomaterials endowed with enzyme-like catalytic activities—have emerged as a transformative approach in modulating AD pathology due to their versatility, catalytic precision, and tunable physicochemical properties. Their therapeutic impact has been realized across several critical pathological dimensions of AD. For instance, in targeting Aβ pathology, nanozymes have demonstrated the capacity to inhibit aggregation and promote disassembly of fibrillar Aβ through a combination of catalytic oxidation and structural disruption. A notable example includes ruthenium (Ru)-based nanoscale MOF (Ru 3+ -NMOFs), developed by Luo and colleagues[39], which exhibit POD-mimetic activity and catalyze the decomposition of excess H 2 O 2 to generate ·OH in Aβ-enriched regions. These reactive species disrupt hydrophobic interactions among Aβ peptides, thereby enhancing solubility and promoting fibril disaggregation with an efficiency increase of up to 67%. Similarly, a multifunctional platform engineered by Ma’s group[97], KD8@N-MCNs, integrates Aβ-targeting peptides with NIR-II-triggered photothermal modules and antioxidative nanozymes. Upon irradiation, localized heating induces the collapse of β-sheet-rich structures, while SOD/CAT-like components simultaneously eliminate ROS, leading to a 52% reduction in hippocampal Aβ burden in AD model mice. Beyond amyloid modulation, nanozymes also address oxidative stress and mitochondrial dysfunction, which are central contributors to neurodegeneration. By mimicking endogenous antioxidant enzymes, nanozymes restore redox balance and mitochondrial integrity. For example, Cu 2 ₋ X Se-TPP nanozymes designed by Wang’s group employ triphenylphosphonium (TPP) ligands for mitochondrial targeting within activated microglia, where they synergistically scavenge ROS and reduce mitochondrial oxidative stress by 78%, effectively breaking the positive feedback loop between oxidative stress and neuroinflammation[32]. In parallel, Pd@PEG@Bor nanozymes synthesized by Liu and colleagues exhibit BBB permeability and rapid accumulation within the brain parenchyma. These nanozymes stabilize intracellular calcium homeostasis, restore mitochondrial membrane potential to 89% of baseline levels, and significantly enhance neuronal cell viability, as demonstrated in SH-SY5Y models[98]. Equally critical is the nanozymes’ capacity to reprogram the neuroinflammatory microenvironment. Intelligent designs, such as Neu-MOF/Fla nanozymes[46], incorporate inflammation-responsive architectures and peptides targeting activated microglia, enabling site-specific action. Upon NIR irradiation, these systems release carbon monoxide (CO) and MOF-based hydrolases in tandem. CO inhibits NLRP3 inflammasome activation, while hydrolase-mediated degradation of proinflammatory mediators facilitates a substantial downregulation of hippocampal TNF-α levels (by 64%) and promotes anti-inflammatory M2 phenotype polarization in 82% of microglial populations. Cu 2 ₋ X Se-TPP nanozymes [32]have also demonstrated the ability to promote M1-to-M2 microglial polarization through mitochondrial ROS clearance, thereby enhancing Aβ phagocytosis by 45% and reinforcing neuroprotective responses. Moreover, the integration of biomimetic strategies with catalytic responsiveness has extended nanozymes’ utility into peripheral Aβ clearance and theranostic applications. Ma’s CuxO@EM-K nanozyme[99], cloaked with red blood cell membranes, not only achieves immune evasion via CD47 expression but also selectively adsorbs plasma Aβ oligomers, increasing peripheral clearance efficiency by 2.3-fold and reducing protein corona formation to 17% ( Figure 2A ). In a parallel development, Zheng’s [41]Pd-Pt/MXene nanozyme combines catalytic and diagnostic capabilities, leveraging POD-like activity to oxidize TMB in the presence of acetylcholinesterase, enabling a highly sensitive colorimetric platform for early detection of acetylcholinesterase inhibitors down to IC₅₀ levels of 0.18 μM, providing critical support for both AD diagnostics and drug discovery. Collectively, these findings underscore the multifaceted and highly modular nature of nanozymes in addressing AD pathology. From molecular-level Aβ disaggregation (e.g., Ru 3+ -NMOFs), organelle-specific oxidative stress modulation (e.g., Cu 2 ₋ X Se-TPP), to systemic neuroinflammatory remodeling (e.g., Neu-MOF/Fla), nanozymes exemplify a new class of precision-engineered therapeutic agents. Coupled with spatiotemporally responsive triggers (e.g., photothermal activation in KD8@N-MCNs), biomimetic camouflage (e.g., erythrocyte membrane-coating in CuxO@EM-K), and diagnostic integration (e.g., Pd-Pt/MXene-based colorimetric platforms), nanozyme-based strategies are rapidly reshaping the therapeutic paradigm for AD toward greater specificity, efficiency, and clinical translation. 4.2.2 Nanozyme-based Therapeutics for PD PD, a chronic and progressive neurodegenerative disorder, is primarily characterized by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta and the pathological aggregation of misfolded α-synuclein (α-syn). In recent years, nanozymes, engineered nanomaterials with enzyme-mimicking catalytic functions and favorable biocompatibility, have demonstrated substantial therapeutic potential in PD through multi-targeted and multi-level interventions. In the context of oxidative stress mitigation, nanozymes mimic endogenous antioxidant enzymes, such as SOD and CAT, to efficiently scavenge ROS and prevent ROS-mediated neuronal damage. Li and colleagues developed a minimally invasive brain-delivery platform based on MFeI microneedles incorporating mitochondria-targeted liposomes encapsulating Fe single-atom nanozymes (Fe-ISAzyme)[100]. Upon accumulation in the substantia nigra and striatum, the Fe-ISAzyme exhibited SOD-CAT cascade activity, enhancing ROS clearance by 4.3-fold and restoring redox balance in affected regions, thereby protecting dopaminergic neurons. Xu’s group further constructed a PtCuSe ternary alloy nanozyme by tailoring intermetallic electronic interactions[40], introducing Cu and Se to create heterogeneous catalytic interfaces that significantly improved enzymatic activity, 2.7-fold over monometallic counterparts, leading to a marked increase in PD neuron survival rates from 48% to 86%. Regarding neuroinflammation and pyroptosis modulation, nanozymes intervene in the activation of NLRP3 inflammasomes within microglia, thereby reshaping the neuroimmune milieu. A PB nanozyme (PBzyme) developed by Ma’s team harnessed the redox cycling between Fe 3+ /Fe 2+ to inhibit NLRP3-ASC complex formation, suppressing caspase-1 activation and IL-1β maturation[101], which in turn reduced dopaminergic neuron loss by 42% in PD mouse models. Expanding upon this strategy, Li’s [44]team engineered a dual-targeted MOF@Man liposomal system combining mannitol-functionalized liposomes for BBB permeability enhancement with an inner zirconium–porphyrin-based MOF (Zr-FeP) exhibiting POD-mimicking activity ( Figure 2C ). This system effectively depleted ROS necessary for inflammasome activation and significantly downregulated NLRP3 and ASC expression, resulting in a 58% reduction in GFAP levels and attenuation of neuroinflammation. To further enhance brain delivery efficiency and enable multimodal synergistic therapy, intelligent nanozyme designs have been introduced. Jiang and colleagues constructed Ptzyme@D-ZIF nanozymes by integrating Pt NPs within a D-configured imidazole-based MOF[69], which activated dual endocytosis pathways via clathrin and caveolin mechanisms, thereby increasing BBB penetration by 3.1-fold and achieving sustained brain retention for up to 72 hours ( Figure 2B ). Within the brain parenchyma, the Pt catalytic centers eliminated lipid peroxides, mitigating ferroptosis and suppressing TNF-α/caspase-8-mediated apoptosis, resulting in significant improvements in PD-related motor dysfunction. In another approach, Ji’s team developed a multifunctional platform, S/Ce-PABMS[102], combining gene interference and nanozyme catalysis. The CeO 2 nanozyme component facilitated Ce 3+ /Ce 4+ cycling for mitochondrial ROS clearance while enabling BBB traversal, while co-delivered siRNA specifically silenced α-syn mRNA translation, reducing aberrant protein aggregation by 76% and restoring motor coordination to 89% of baseline levels in PD mice. Collectively, nanozymes offer a multifaceted therapeutic framework for PD, spanning molecular-scale redox modulation (e.g., PtCuSe catalytic cascades), organelle-specific protection (e.g., Fe-ISAzyme targeting mitochondrial oxidative stress), and systemic immune microenvironment reprogramming (e.g., PBzyme inhibition of NLRP3 activation). Leveraging advanced delivery technologies (such as the MFeI microneedle platform), biomimetic material engineering (as exemplified by Ptzyme@D-ZIF), and combinatorial intervention strategies (such as the catalytic–gene co-therapy of S/Ce-PABMS), nanozymes are poised to redefine the paradigm of precision nanomedicine in PD and accelerate their translational potential toward clinical application. 4.2.3 Nanozyme-Mediated Modulation of Neuroinflammation Neuroinflammation, a shared pathological hallmark across multiple central nervous system (CNS) disorders such as AD, PD, and stroke, represents a critical therapeutic challenge requiring precise intervention. Nanozymes, endowed with programmable catalytic activities, multi-mechanistic regulatory capacities, and excellent biocompatibility, have emerged as promising agents for modulating neuroinflammatory processes. Their mechanisms of action span reactive oxygen and nitrogen species (RONS) scavenging, inhibition of inflammatory signaling pathways, immune microenvironment remodeling, and enhanced targeted delivery, thus bridging fundamental research and preclinical translation. In the disruption of the oxidative-inflammation positive feedback loop via RONS clearance, Gong and colleagues engineered a Se@PDA@Bor nanozyme comprising a selenium core stabilized within polydopamine, functionalized with boronic acid moieties for specific recognition of Aβ[103]( Figure 2D ). The catalytic activity of the selenium centers, modulated by Se⁴⁺/Se⁶⁺ valence states, efficiently decomposed ONOO⁻, reducing intracellular RONS by up to 76% and effectively interrupting the Aβ-induced oxidative-inflammatory cascade. Concurrently, this system restored mitochondrial membrane potential (ΔΨm increased 2.3-fold) and promoted microglial polarization toward the anti-inflammatory M2 phenotype, enhancing Aβ phagocytosis by 3.1-fold. In AD mouse models, these effects translated into a 58% improvement in cognitive performance, validating the dual redox-immunomodulatory efficacy of the platform. Addressing immune phenotype remodeling and inflammasome inhibition, Huang’s group[104] developed NM@Fe-DMY biomimetic nanozymes cloaked with neutrophil membranes for active targeting of inflamed brain regions. The iron core mimics SOD and CAT activities, rapidly scavenging O 2 •⁻ and H 2 O 2 , while the self-assembled dihydromyricetin (DMY) ligands upregulate glutathione peroxidase 4 expression to enhance detoxification of lipid peroxides, collectively lowering malondialdehyde (MDA) levels by 64%. Crucially, this nanozyme suppressed TLR4/NF-κB pathway activation, inducing microglial shift from pro-inflammatory M1 to anti-inflammatory M2 phenotypes, evidenced by an 82% decrease in CD86 and a 2.7-fold increase in CD206 expression. In subarachnoid hemorrhage models, it effectively alleviated cerebral edema with a 47% volume reduction, demonstrating comprehensive immune reprogramming capacity. To overcome the BBB and achieve precise brain parenchymal delivery, Li’s team[69] designed chiral MOF-based Ptzyme@D-ZIF nanozymes. Constructed with D-configured imidazole linkers, this platform enhanced BBB penetration via clathrin- and caveolin-mediated dual endocytosis pathways, improving translocation efficiency by 3.8-fold relative to conventional carriers and prolonging cerebral retention. Within neural tissue, the Pt nanozyme exhibited GPx-like activity, scavenging lipid peroxides and significantly reducing the core components of NLRP3 inflammasomes: ASC speck formation decreased by 71%, and caspase-1 activation was suppressed by 63%. In PD models, this intervention effectively blocked IL-1β-mediated neuronal damage, resulting in an 89% improvement in rotational motor behavior, highlighting its potent anti-inflammatory and neuroprotective capabilities. Furthermore, Gao’s group[105] developed a multifunctional nanozyme platform (PMC NPs) stabilized by manganese-polyethyleneimine coordination networks and co-loaded with the anti-inflammatory small molecule curcumin. The manganese centers catalyze O 2 •⁻ dismutation with a rate constant of 2.1 × 10 9 M⁻¹·s⁻¹, while curcumin coordinates with manganese to stabilize its oxidation state and inhibit NF-κB nuclear translocation, thereby establishing a catalytic-drug synergistic mechanism. This system markedly reduced TNF-α secretion from microglia by 84% and restored neuronal viability by 41.7% under lipopolysaccharide-induced injury through modulation of mitochondrial calcium homeostasis (intracellular Ca 2+ reduced to 126 nM), offering a novel paradigm for combined anti-inflammatory and neuroprotective therapies. Nanozymes are advancing from passive mitigation toward active and precise regulation of neuroinflammation. From valence-tunable RONS scavenging (e.g., Se@PDA@Bor) and immune phenotype reprogramming (e.g., NM@Fe-DMY), to targeted inflammatory signaling inhibition (e.g., Ptzyme@D-ZIF) and drug co-delivery strategies (e.g., PMC NPs), these innovations exemplify the integration of material design and biological functionality. Collectively, they underscore the evolving potential of nanozymes as versatile and efficacious nanomedicines for the treatment of neurodegenerative and neuroinflammatory disorders. Figure 2 ( A ). Schematic representation of the synthesis process of CuxO@EM-K and its mechanism of facilitating peripheral amyloid-beta (Aβ) clearance[99]. Copyright 2020 American Chemical Society. ( B ). Illustrative diagram of Ptzymes integrated within L- and D-chiral zeolitic imidazolate frameworks (ZIFs), depicting their therapeutic effects in PD through simultaneous mitigation of neuronal apoptosis and ferroptosis induced by excessive ROS and dysregulated inflammatory responses[69]. Copyright 2023 Springer Nature. ( C ). Visual overview of the preparation methodology for the MOF@Man Liposome nanozyme system, elucidating its therapeutic approach for PD treatment by reducing oxidative stress and neuroinflammation.This is achieved through inhibition of NLRP3 inflammasome formation and suppression of inflammatory cytokine secretion[44]. Copyright 2023 Wiley-VCH GmbH. ( D ). Comprehensive schematic of the study, highlighting how Se@PDA@Bor protects neural cells by alleviating Aβ accumulation and modulating neuroinflammatory processes. The nanoconstruct facilitates phenotypic switching of microglia from a pro-inflammatory M1 to an anti-inflammatory M2 state by scavenging ROS/RNS, thereby enhancing Aβ clearance efficiency[103]. Copyright 2021 Elsevier B.V. 4.3 Metabolic Diseases 4.3.1 Treatment of Diabetic Wounds The core pathological mechanisms underlying impaired healing of chronic diabetic wounds predominantly arise from sustained hyperglycemia-induced accumulation of ROS, persistent unresolved chronic inflammation, inhibited angiogenesis, and disrupted extracellular matrix (ECM) remodeling[106]. These interrelated pathological factors collectively establish a highly complex wound microenvironment refractory to repair. In this context, nanozymes endowed with multi-enzyme mimetic activities, owing to their superior stability, tunability, and catalytic efficiency, have emerged as promising therapeutic agents for modulating the diabetic wound milieu and accelerating tissue regeneration. Central to nanozyme intervention is the scavenging of excessive ROS to alleviate oxidative stress. Diabetic wound tissues are characterized by continuous accumulation of O 2 •⁻ , H 2 O 2 , and ·OH, which directly compromise cell membrane integrity, induce mitochondrial dysfunction, and activate diverse pro-inflammatory signaling cascades. Nanozymes mimic natural antioxidant enzymes such as SOD, CAT, and GPx to catalytically decompose ROS with high efficiency. For instance, Feng et al. [34]developed GOZCR smart hydrogels incorporating Cu-rhein nanosheets exhibiting SOD-like activity capable of concurrently scavenging O 2 •⁻ and ·OH radicals. Wang et al. [107]reported a GNR@CeO 2 @GNPs composite nanozyme whose CeO 2 shell demonstrated a 4.7-fold enhancement in CAT/SOD mimetic activity under near-infrared (NIR) plasmonic excitation ( Figure 3A ). Dai’s [37]Zn/C-dots nanozymes presented a synergistic SOD/CAT/GPx triple-enzyme mimicry, boosting total antioxidant capacity by 8.7-fold and restoring mitochondrial membrane potential (ΔΨm increased by 83%) to confer cytoprotection ( Figure 3B ). Moreover, CoNZ[108] nano-glass generates Co 3 O 4 nanocrystals in situ under H 2 O 2 stimulation, efficiently scavenging O 2 •⁻ and ·OH with respective efficiencies of 92% and 87%. The PB-Zr nanozyme notably suppressed NLRP3 inflammasome activation, reducing caspase-1 activity by 62%, further substantiating the pivotal role of ROS clearance in inflammation modulation. Beyond ROS scavenging, nanozymes actively regulate inflammation by reprogramming immune cell phenotypes to facilitate resolution and restore immune homeostasis. PB-Zr nanozymes induced macrophage polarization toward a reparative M2 phenotype via STAT6 pathway activation, elevating CD206⁺ cell proportion from 18% to 53% and markedly suppressing pro-inflammatory cytokines IL-17 and IL-23 by 4- to 7-fold[109]. Pu and colleagues’ [110]AHAMA/CS-GOx@Zn-POM hydrogels released Zn 2+ during the repair phase to further promote M2 polarization (Arg1/CD206 expression increased 3.2-fold), concurrently inhibiting IL-17A expression via p38 MAPK pathway suppression (downregulated by 68%). The CoNZ system attenuated inflammation by suppressing NF-κB-mediated cytokine expression, including TNF-α and IL-6 reductions of 68% and 54%, respectively. In terms of angiogenic regulation, activation of the HIF-1α/VEGF signaling axis remains critical for enhancing neovascular density. The CoNZ nanozyme sustainedly released Co 2+ , stabilizing HIF-1α expression and significantly promoting endothelial cell migration (2.4-fold increase) and capillary formation (178% increase in vessel density). Both PB-Zr and Cu 2 ₋ X Se-BSA nanozyme[111] systems stimulated the HIF-1α/VEGF pathway via Cu 2+ or photoexcited intermediates, augmenting vascular density by 2.3- and 2.16-fold, respectively. Dai’s[37] Zn/C-dots nanozymes upregulated MMP-2 expression through Zn 2+ release, enhancing endothelial migration with a scratch wound closure rate elevated by 216%. Pu’s Zn-POM hydrogel further demonstrated a 194% increase in neovascular branching as evidenced by Micro-CT imaging. Addressing bacterial infection—a critical impediment in diabetic wound healing—nanozymes leverage pathogen-responsive antimicrobial mechanisms and multifaceted killing pathways. Zn 2+ released from GOZCR hydrogels exhibited potent antibacterial effects, responsive to acidic and oxidative microenvironments, thereby enabling an integrated “environment sensing–anti-inflammatory–antibacterial–pro-healing” therapeutic cascade[34]. The GNR@CeO 2 @GNPs system generated 1 O 2 under NIR irradiation and glucose stimulation, achieving 99.2% clearance of MRSA biofilms[107]. OBG@CG hydrogels catalyzed glucose oxidation to produce H 2 O 2 [111], activating Cu 2 ₋ X Se-BSA nanozyme POD-like activity and yielding ·OH radicals that degraded biofilms with 92.4% efficacy. Shen’s [112]FeSN-aerogel combined GOx and FeSN cascade catalysis to kill MRSA at 98.3% efficiency in acidic conditions while reducing local glucose by 76%.[113]Furthermore, nanozymes contribute to ECM remodeling and wound closure. OBG@CG hydrogels released Cu 2+ ions that not only enhanced angiogenesis but also significantly promoted type III collagen synthesis (increased by 194%). GOZCR hydrogels similarly facilitated collagen deposition, improving tissue mechanical integrity. Overall, nanozymes, via their multi-enzyme mimetic functions, orchestrate a multifaceted therapeutic paradigm in diabetic wound microenvironment modulation, encompassing antioxidation, anti-inflammation, pro-angiogenesis, antimicrobial activity, and ECM remodeling. Representative nanozyme platforms such as GOZCR, GNR@CeO 2 @GNPs, OBG@CG, CoNZ, PB-Zr, Zn/C-dots, FeSN-aerogel, AHAMA/CS-GOx@Zn-POM, and APGH have demonstrated significant therapeutic efficacy in animal models, reducing wound healing time by 37–40% and increasing vascular density by 2.3–2.8 fold, thereby providing a robust nanomedicine-based foundation for addressing the clinical challenges of diabetic infected wounds. 4.3.2 Diabetic Retinopathy Nanozymes intervene deeply in the complex pathophysiology of diabetic retinopathy (DR) through multidimensional synergistic mechanisms, demonstrating unique advantages as novel precision therapeutic platforms. Central to their antioxidative defense is the efficient scavenging of excessive ROS accumulated in lesion sites, thereby directly preventing ROS-induced lipid peroxidation, protein denaturation, and DNA damage. Moreover, nanozymes activate endogenous antioxidative signaling pathways, notably inducing the Nrf2 pathway, which upregulates downstream antioxidant gene expression and enhances retinal cellular resilience. For instance, Gui et al.[114] developed Fe-Quer nanozymes—ultrasmall (<5 nm) biomimetic nanodots formed via coordination between Fe 3+ and quercetin—exhibiting SOD, CAT, and POD-like activities that broadly scavenge O 2 •⁻ and H 2 O 2 , effectively restoring redox homeostasis in retinal tissues ( Figure 3C ). Transcriptomic analyses further revealed that these nanozymes modulate the HIF-1α/NF-κB crosstalk axis, synergistically suppressing oxidative stress, inflammation, and vascular leakage, key early pathological events in DR, highlighting their transformative potential in ROS-driven ocular disease therapy. At the anti-inflammatory and immunomodulatory level, nanozymes efficiently disrupt activation cascades of core pro-inflammatory pathways such as NF-κB, markedly downregulating cytokines including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), thus alleviating retinal inflammation. They also promote macrophage polarization towards the reparative M2 phenotype, fundamentally ameliorating the chronic inflammatory microenvironment and fostering tissue repair. Fe-Quer nanozymes notably exhibit potent inflammation modulation, reinforcing their multi-modal intervention capabilities[114]. Addressing the highly heterogeneous vascular homeostasis disturbances characteristic of DR, namely, ischemic hypoperfusion coexisting with pathological neovascularization, nanozymes demonstrate bidirectional regulation: enhancing ischemic tissue perfusion and oxygen supply while selectively inhibiting aberrant angiogenesis via suppression of the HIF-1α/VEGF axis. Tian et al. [115]reported copper nanodots possessing CAT/SOD-mimetic activities that effectively scavenge ROS and mitigate hypoxia, concomitantly repressing pathological VEGF expression to inhibit neovascular formation and leakage. Both in vitro and in vivo studies confirmed that Cu nanodots eye drops significantly protect human retinal microvascular endothelial cells with excellent biocompatibility and localized safety. Additionally, Zhou et al. [116]designed a photosynthetic hybrid system (Cyano@Au@Ir) integrating glucose oxidase (GOD)-like Au NPs with CAT-like iridium NPs (Ir NPs), enabling cascade catalysis for enzymatic glucose degradation under hyperglycemic conditions (Au NPs generate H 2 O 2 ) and subsequent oxygen generation (Ir NPs convert H 2 O 2 into O 2 and H 2 O). This system simultaneously achieves ROS clearance, localized oxygen supply, and glucose metabolism regulation, effectively attenuating neovascularization and vascular permeability in animal models, thereby establishing a new paradigm for precision modulation of the diabetic microenvironment. At the cellular protection and tissue repair level, nanozymes activate survival signaling pathways such as PI3K/Akt, promoting the survival and functional restoration of retinal neurons and vascular endothelial cells, thus supporting tissue regeneration and functional recovery. To enhance lesion-specific delivery and therapeutic targeting, nanozymes are frequently functionalized with targeting moieties, such as folate receptors or anti-VEGF antibodies, thereby improving selective accumulation in diseased retinal tissues and minimizing off-target toxicity. Nanozymes orchestrate a multi-mechanistic, synergistic intervention of the pathological network underlying diabetic retinopathy, including efficient ROS scavenging (e.g., the tri-enzymatic activities of Fe-Quer nanozymes), inflammation microenvironment remodeling (NF-κB inhibition and M2 polarization induction), precise vascular homeostasis regulation (HIF-1α/VEGF axis blockade by Cu nanodots, hypoxia, and oxidative stress alleviation by Cyano@Au@Ir), and promotion of neurovascular repair. This integrated biointelligent therapeutic strategy offers a pioneering approach for the precise treatment of DR and other metabolic ocular diseases. math_shortcuts 4.3.3 Insulin Resistance (IR) IR constitutes a central pathological basis of diabetes and its associated metabolic disorders. Recently, nanozymes endowed with multi-enzyme mimetic activities and multi-target regulatory capabilities have emerged as promising agents for intervening in IR. Their therapeutic mechanisms encompass multiple dimensions, including oxidative stress alleviation, mitochondrial function restoration, inflammatory pathway inhibition, and glucose metabolic signaling remodeling, collectively demonstrating potential for systemic metabolic homeostasis regulation. Regarding oxidative stress mitigation and mitochondrial repair, nanozymes mimic SOD and CAT activities to efficiently scavenge intracellular ROS, thereby interrupting ROS-mediated impairment of insulin signaling cascades. Wang et al.[117] engineered polyacrylic acid-modified CeO 2 nanozymes (PCNPs) exhibiting robust dual SOD/CAT-like activities, which significantly restored mitochondrial membrane potential by 2.1-fold and reduced the senescence marker p16 expression by 58% in bone marrow mesenchymal stem cells derived from type 2 diabetes mellitus models. This effect was mediated via activation of the AMPK–SIRT1–PGC1α axis, enhancing mitochondrial biogenesis and function. In vivo studies further confirmed the cross-system synergistic therapeutic efficacy of PCNPs, which not only accelerated bone defect healing through controlled release but also markedly reduced body weight (by 21%) and fasting blood glucose levels (by 26%) in ob/ob mice, significantly ameliorating IR and metabolic syndrome phenotypes. Li et al. [118]developed ultrasmall CeO 2 nanozymes with mitochondria-targeting capability that notably decreased ROS production by 64%, enhanced ATP synthesis by 1.8-fold, and repaired mitochondrial cristae structures in offspring of gestational diabetes mellitus models. Consequently, skeletal muscle insulin sensitivity was improved, as evidenced by a 45% increase in glucose uptake. These interventions enhanced offspring exercise endurance by 2.3-fold and reduced HOMA-IR indices by 39%, providing a novel paradigm for intergenerational metabolic disease management. At the level of inflammation and insulin signaling reconstruction, nanozymes suppress key pro-inflammatory pathways such as NF-κB, thereby reducing secretion of cytokines, including TNF-α and IL-6, mitigating chronic low-grade inflammation that disrupts insulin signaling. Shen et al. [119]developed a tri-metallic Au-Ce-Pt synergistic cascade nanozyme (AuCePt PHNs) featuring a hollow porous architecture, SOD/CAT-like activities, and drug loading capacity ( Figure 3D ). By functionalizing with lactobionic acid and loading disulfiram (DSF) to form AuCePt PHNs-LA@DSF, they achieved significant enhancement of glucose uptake (37%) and glycogen synthesis (42%) in insulin-resistant hepatocytes. Mechanistically, this system activated the IRS-1/AKT signaling axis to potentiate insulin transduction while concurrently inhibiting the FOXO-1/PEPCK-mediated gluconeogenic pathway, thereby reversing IR at multiple regulatory nodes. In vivo administration via intravenous injection demonstrated liver-specific targeting, leading to significant reductions in body weight (18%) and fasting glucose (32%) alongside improved hepatic steatosis in high-fat diet and ob/ob mouse models, exemplifying a liver-targeted precision therapeutic approach for IR. Furthermore, Lin et al.[120] designed single-atom catalytic Ce-N-C nanozymes (SACe-N-C) exhibiting pronounced dual functionalities: activation of the PI3K/AKT/GSK3β signaling pathway to augment glucose uptake and glycogen synthesis, coupled with induction of the Keap1/Nrf2 antioxidant pathway to elevate endogenous enzyme activities such as SOD and GPx. This coordinated modulation optimizes both glucose metabolism and oxidative stress environments. In type 2 diabetes mellitus mouse models, SACe-N-C treatment markedly decreased fasting blood glucose by 29%, increased hepatic glycogen content by 17.13%, enhanced insulin secretion by 18.87%, and significantly elevated SOD and GPx activities by 17.80% and 25.28%, respectively, indicating effective disruption of the pathological positive feedback loop in IR via a metabolically coupled redox regulatory network. Nanozymes exhibit integrated therapeutic potential in IR intervention through multidimensional synergistic mechanisms, including ROS scavenging and mitochondrial repair (e.g., PCNPs, ultrasmall CeO 2 ), inflammatory pathway inhibition and insulin signaling activation (e.g., AuCePt PHNs-LA@DSF), and dual enhancement of glucose metabolism and antioxidative capacity (e.g., SACe-N-C). These intelligent nano-catalytic platforms not only provide powerful tools for elucidating the molecular pathology of IR but also offer highly feasible nanomedicine strategies for the precise treatment of diabetes and metabolic syndrome. math_shortcuts 4.3.4 Hypertension Hypertension is a highly complex vascular dysfunction disorder, intimately associated with sustained oxidative stress. During disease progression, excessive accumulation of ROS not only disrupts the integrity of the vascular endothelium but also promotes vascular smooth muscle cell remodeling, ultimately leading to reduced vascular compliance and persistently elevated blood pressure. In recent years, nanozymes with enzyme-like catalytic activities have demonstrated unique therapeutic advantages in hypertension management due to their ability to target multiple pathways and biological processes. To alleviate oxidative stress, nanozymes can mimic the catalytic activities of various endogenous antioxidant enzymes, including SOD, CAT, GPx, and POD, thereby facilitating the coordinated elimination of O 2 •⁻ and H 2 O 2 . This synergistic ROS scavenging significantly improves endothelium-dependent vasodilation. For example, a two-dimensional niobium carbide-based MXene nanozyme (Nb 2 C MXenzyme) developed by Yang and colleagues exhibited broad-spectrum enzyme-mimetic activity and enabled efficient ROS clearance via cascade catalytic reactions[121] ( Figure 3E ). In stress-induced hypertension animal models,intracerebroventricular administration of the Nb 2 C MXenzyme led to a ~28% and respectively, while effectively inhibiting NADPH OXD-driven oxidative damage signaling and restoring normal vascular physiology. Beyond its antioxidative properties, Nb 2 C MXenzyme also plays a pivotal role in neural regulation. Hyperactivation of the sympathetic nervous system is a core mechanism in neurogenic hypertension. Remarkably, this nanozyme substantially suppressed renal sympathetic nerve activity, reducing its amplitude by approximately 64%, thereby alleviating sympathetic overdrive. Moreover, it promoted microglial remodeling in the prefrontal cortex, increasing dendritic complexity by 2.1-fold and axonal density by 37%, thereby enhancing neural network plasticity. In parallel, the nanozyme downregulated caspase–3–dependent apoptotic signaling (activity decreased by This integrated mechanism of ”antioxidation–anti-inflammation–neuroregeneration” presents a novel paradigm for neuromodulatory intervention in hypertension. In terms of anti-inflammatory and vasoprotective effects, nanozymes mitigate endothelial inflammatory responses by scavenging ROS and subsequently suppressing the activation of pro-inflammatory signaling cascades, such as the NF-κB and MAPK pathways. This results in reduced expression of pro-inflammatory cytokines, including TNF-α and IL-6, and alleviates the inflammatory vascular microenvironment. Notably, Nb 2 C MXenzyme also disrupts the ROS-driven positive feedback loop by inhibiting persistent NADPH OXD activation and restoring endothelial NO synthase functionality, thereby increasing NO bioavailability and further improving vasodilation and hemodynamic stability. Collectively, nanozyme-based platforms, particularly the Nb 2 C MXenzyme system, offer a promising avenue for precision therapy of hypertension, owing to their multifaceted intervention capabilities in ROS scavenging, neurofunctional remodeling, and vascular protection. This pathophysiology-informed, multi-targeted therapeutic strategy not only enables effective blood pressure reduction but also holds the potential to halt or reverse disease progression, underscoring significant prospects for clinical translation. 4.3.5 Non-alcoholic Fatty Liver Disease (NAFLD) NAFLD, a prevalent metabolic liver disorder, is governed by a complex interplay of oxidative stress, chronic inflammation, and progressive hepatic fibrosis. Given the multifactorial pathogenesis and the growing demand for multi-targeted interventions, nanozymes with enzyme-mimicking catalytic activity have emerged as a promising therapeutic modality. Leveraging their biomimetic enzyme functionality and precise regulatory capacity, nanozymes offer the potential for systemic intervention across key pathological processes of NAFLD. In terms of antioxidation and hepatoprotection, nanozymes can efficiently scavenge ROS and lipid peroxides by mimicking the catalytic activity of endogenous enzymes such as SOD and CAT, thereby restoring redox homeostasis and alleviating oxidative stress-induced hepatocellular injury. For instance, a metal–phenolic network-based nanozyme (CA-Mn NPs) developed by Wang et al. [35]exhibits precise SOD- and CAT-like catalytic behavior, significantly reducing ROS accumulation in hepatic tissue. Mechanistically, CA-Mn NPs modulate both the Nrf2–Keap1 and NF-κB p65 signaling axes, suppressing hepatocyte apoptosis and downregulating pro-inflammatory cytokines such as TNF-α and IL-6. This dual “antioxidant–anti-inflammatory” defense barrier contributes to effective hepatic functional recovery. From the perspective of immune modulation and inflammation resolution, nanozymes have demonstrated the capacity to reshape the hepatic immune microenvironment and reverse the immune dysregulation characteristic of NAFLD. CA-Mn NPs effectively regulate macrophage polarization, promoting a phenotypic shift from pro-inflammatory M1 to anti-inflammatory M2 macrophages, thereby attenuating cytokine release and improving local tissue homeostasis. Building on this strategy, Yang et al. [122]engineered a HA-templated HCOL liposomal nanozyme system, which achieved more precise control of macrophage reprogramming. This design not only enhanced anti-inflammatory efficacy but also promoted liver regeneration, disrupting the inflammation-driven pathological feedback loop. In the context of anti-fibrotic therapy and metabolic homeostasis regulation, nanozymes suppress hepatic stellate cell (HSC) activation, thereby halting collagen deposition and potentially reversing fibrotic remodeling. The HCOL system, for example, reduces ROS levels within HSCs and attenuates TGF–β–associated fibrotic signaling, exerting a potent anti-fibrotic effect. Furthermore, Sun et al. [123]designed CeO 2 nanozymes (CeO 2 NPs) that leverage oxygen vacancy–mediated catalysis to convert L-arginine into NO and its bioactive derivatives. This not only enhances hepatic microcirculation and vasodilation but also modulates macrophage metabolism and improves dyslipidemia, collectively contributing to the inhibition of atherosclerotic plaque formation. This multifunctional therapeutic model, integrating antioxidant, anti-inflammatory, and anti-fibrotic effects, comprehensively targets the major pathological dimensions of NAFLD ( Figure 3F ). Next-generation nanozyme platforms such as CA-Mn NPs, HCOL systems, and CeO 2 NPs exemplify a multidimensional therapeutic approach capable of relieving NAFLD symptoms and altering disease progression. Centered on biomimetic catalysis, these systems construct a precise and synergistic intervention strategy, offering an advanced and translationally viable solution for the treatment of NAFLD and associated metabolic disorders. Figure 3 ( A ). Schematic illustration of the fabrication process and antibacterial application of GNR@CeO2@GNPs bio-cockleburs[107]. Copyright 2024 Wiley-VCH GmbH. ( B ). Schematic illustration of the preparation of multifunctional hydrogels loaded with Zn/C-dots and the repair of diabetic wounds[37]. Copyright 2024 Acta Materialia Inc. ( C ). Process flowchart for the preparation of Fe-Quer nanozymes (NZs).Fe-Quer NZs function as microvasculo-protective agents with multifunctional nanozyme activities, including SOD, CAT and POD.They possess excellent water dispersibility, efficient ROS scavenging capability and exhibit anti-microvascular leakage, anti-microangioma and anti-angiogenic effects, making them suitable for the treatment of DR[114]. Copyright 2023 Wiley-VCH GmbH. ( D ). Schematic illustration of the fabrication of AuCePt PHNs-LA@DSF nanocomposites and the targeted amelioration of hepatic ischemia-reperfusion injury by AuCePt PHNs-LA@DSF[119]. Copyright 2024 BMC. ( E ). Schematic diagram of the exfoliation and disintegration process of ultrathin Nb2C MXene derived from bulk Nb2AlC ceramics through hydrofluoric acid (HF) etching and tetrapropylammonium hydroxide (TPAOH) intercalation.Schematic representation of 2D Nb2C MXene,which exhibits multiple enzyme-like activities such as SOD,CAT,GPx, and POD,enabling it to catalyze ROS scavenging, suppress inflammation, and reverse the progression of steroid-induced osteonecrosis (SIH) in rats[121]. Copyright 2023 Wiley-VCH GmbH. ( F ). Illustrates that lipid deposition and macrophage infiltration in vascular walls can lead to abnormal NO secretion mediated by endothelial nitric oxide synthase (eNOS) in endothelial cells, thereby exacerbating inducible nitric oxide synthase (iNOS)-mediated pro-inflammatory responses in macrophages. This creates a feedback loop promoting vascular plaque formation. Depicts that ceria nanoparticles (CeO 2 NPs) with NOS-like activity can enhance serum NO levels, mimicking the function of NOS to elevate NO levels. This exogenous NO supplementation can improve endothelial and macrophage function, prevent vascular plaque formation, and modulate blood lipid distribution and cell function by altering hemodynamic parameters such as blood flow shear stress[123]. Copyright 2023 BMC. 11pt, fleqn, a4paper, ]LegrandOrangeBook 4.4 IBD 4.4.1 Nanozyme-based Therapeutics for Crohn’s Disease and Ulcerative Colitis IBD, encompassing Crohn’s disease and ulcerative colitis, is driven by a multifactorial pathogenesis involving oxidative stress, inflammatory cascades, dysbiosis, and disruption of the intestinal barrier. Nanozymes, endowed with enzyme-mimicking catalytic properties, have emerged as a promising therapeutic modality capable of multi-target intervention, offering a novel avenue for IBD management. In the regulation of oxidative stress, nanozymes demonstrate robust activity in scavenging RONS, thereby mitigating oxidative injury–induced inflammation. Liu and colleagues developed [45]a Pt@PCN222-Mn nanozyme based on a MOF scaffold, in which Pt single atoms and manganese porphyrins act synergistically to confer cascade SOD- and CAT-like activities. This system efficiently converts O 2 •⁻ to H 2 O 2 and subsequently decomposes it into water and oxygen, resulting in a 62% reduction in MDA levels at inflammatory sites. In another approach, Chen’s group constructed a Spirulina-derived CeO 2 -based nanozyme (SP-CeO 2 ), which combines the biocompatibility of the algal scaffold with the redox cycling of Ce 3+ /Ce 4+ . In a murine colitis model, SP-CeO 2 significantly decreased levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) by 58%, effectively suppressing oxidative DNA damage. In the modulation of gut microbiota, nanozymes offer precision-targeted strategies. Dong’s group [124]designed a PB@N3 system that integrates the ROS-scavenging capability of PB with a click-chemistry–enabled delivery mechanism. This system selectively binds DBCO-modified Lactobacillus reuteri (LR@DBCO) at inflamed sites, prolonging probiotic colonization beyond 72 hours and suppressing pathogenic E. coli overgrowth (3.2-fold reduction in abundance). Jiang’s team[125] developed a two-dimensional WSe 2 @F127 nanozyme via liquid-phase exfoliation, which releases W⁶⁺ ions exhibiting potent antibacterial activity (89% inhibition rate) and engages in Se⁴⁺/Se⁶⁺ redox cycling to synergistically clear RONS ( Figure 4B ). This treatment restored gut microbial α-diversity to 85% of normal levels. For inflammatory signaling modulation, Zeng et al. [126]synthesized CeNP-PEG, a PEGylated CeO 2 nanozyme with enhanced colonic retention. This nanozyme not only scavenged ROS but also directly bound to the p65 subunit of NF-κB, preventing its nuclear translocation and resulting in 74% and 68% reductions in TNF-α and IL-6 mRNA levels, respectively. Moreover, it suppressed JAK2/STAT3 activation and decreased the proportion of pro-inflammatory Th17 cells (from 23.5% to 9.8%), leading to a 65% improvement in disease activity index (DAI) scores in DSS-induced colitis models. In response to neutrophil extracellular traps (NETs)—a recently recognized amplifier of intestinal inflammation—Wang’s group [127]constructed a DNase-NZ system by covalently conjugating DNase I to a PLGA-based carrier. This platform maintained enzymatic activity under colonic acidic conditions (92% retention) and specifically degraded the DNA backbone of NETs, lowering MPO–DNA complex levels by 81% ( Figure 4A ). In TNBS-induced colitis models, DNase-NZ treatment reduced tissue damage scores by 58%, effectively interrupting NET-mediated chronic inflammation loops. For intestinal barrier restoration, the WSe 2 @F127 nanozyme significantly upregulated tight junction proteins ZO-1 and occludin, elevating transepithelial electrical resistance to 210 Ω·cm²—approaching the baseline of healthy epithelium (230 Ω·cm²). Simultaneously, the PB@N3 system promoted goblet cell–mediated secretion of mucin-2, restoring the colonic mucus layer thickness from 25 μm (inflammatory state) to 55 μm, thereby reinforcing the physical barrier function. Collectively, these findings underscore the potential of nanozymes to orchestrate multi-dimensional therapeutic actions in IBD. Through biomimetic catalytic cascades (e.g., Pt@PCN222-Mn), microbiota-targeted delivery (e.g., PB@N3), and immune-mucosal barrier reconstruction (e.g., WSe 2 @F127), nanozymes enable molecular-level control of oxidative stress, microbial balance, and inflammatory signaling. Advances in structural design, surface engineering, and targeted delivery collectively establish nanozymes as a transformative paradigm for systemic, multi-targeted IBD intervention with strong translational potential. 4.4.2 The Role of Nanozymes in Intestinal Barrier Protection Nanozymes exhibit a multifaceted and synergistic regulatory capacity in the protection of intestinal barrier function, acting through the integrated modulation of oxidative stress, immune homeostasis, and mucosal tissue regeneration. Central to these effects is their capacity to intervene in key pathophysiological processes underpinning barrier disruption. At the antioxidant defense level, nanozymes can mimic the activity of natural antioxidant enzymes such as SOD, CAT, and GPx, enabling efficient clearance of locally accumulated ROS in the gut. Zhu and colleagues [128]developed a selenium-zero-valent PB nanozyme (Se-HMPB), which integrates the CAT-like activity of PB with GPx-mimicking functionality imparted by surface-bound elemental selenium ( Figure 4C ). This synergistic catalytic system efficiently decomposes H 2 O 2 and selectively eliminates lipid hydroperoxides at inflammatory sites. In a Crohn’s disease animal model, Se-HMPB treatment reduced MDA levels in intestinal tissue by 67%, thereby halting ferroptosis progression. Concurrently, the nanozyme modulated the Th17/Treg axis by decreasing Th17 cell proportion by 42%, restoring immune homeostasis and reinforcing both the mechanical and immunological integrity of the intestinal barrier. In terms of immune regulation, nanozymes can target key inflammatory signaling pathways to precisely modulate chronic mucosal inflammation. Zhang’s group[129] developed an iron oxide–chitosan nanocomposite encapsulated in Eudragit S100 (ES-IOCS), which demonstrates dual repair effects on the physical and immune barriers. First, it promotes the expression of tight junction proteins such as claudin-1 and occludin in epithelial cells—upregulated by 2.3-fold and 1.8-fold, respectively—thus strengthening epithelial integrity. Second, it suppresses activation of the NLRP3 inflammasome, reducing IL-1β secretion by 58% and thereby mitigating immune overactivation and tissue injury. In a murine model of ulcerative colitis, ES-IOCS displayed potent anti-inflammatory effects and tissue repair capacity, highlighting its translational potential in precise immune modulation. Additionally, nanozymes contribute to barrier reconstruction by regulating the cellular metabolic microenvironment and accelerating mucosal regeneration. Zhang and colleagues developed [130]PEGylated CeO 2 nanozymes (PEG-CNPs), which possess cascade-like SOD and CAT enzymatic activities, enabling sustained scavenging of ROS within epithelial cells ( Figure 4D ). Moreover, PEG-CNPs suppressed the overexpression of hypoxia-inducible factor-1α (HIF-1α) by 45%, alleviating hypoxia in the inflamed mucosa. Simultaneously, the nanozyme inhibited the activation of pro-inflammatory M1 macrophages, reducing the proportion of CD86⁺ cells by 62%. These combined actions contributed to metabolic rebalancing and robust enhancement of barrier function. Collectively, these advances illustrate the systemic protective potential of nanozymes in intestinal barrier maintenance via multi-targeted mechanisms. From efficient ROS scavenging and precise regulation of inflammatory pathways to dynamic structural restoration of the mucosal barrier, nanozymes offer a bioactive and delivery-specific material strategy. This integrated approach opens new avenues for the comprehensive treatment of IBD. Figure 4 ( A ). Schematic illustration of the fabrication and application of DNase-NZ in colitis treatment[127]. Copyright 2024 Springer Nature. ( B ). Schematic illustration of the synthesis and therapeutic effect of WSe2@F127 in an IBD model[125]. Copyright 2023 Wiley-VCH GmbH. ( C ). Schematic diagram of Se-HMPB nanozyme in reconstructing the intestinal barrier against IBD by scavenging ROS, inhibiting ferroptosis, and modulating T cell differentiation[128]. Copyright 2023 Wiley-VCH GmbH. ( D ). Restoration of the dysregulated intestinal barrier and inflammatory response using ceria nanozymes for ulcerative colitis treatment.The therapeutic mechanism of PEG-CNPs involves synergistically alleviating hypoxia and scavenging ROS through SOD/CAT activity[130]. Copyright 2023 BMC. 4.5 Skin Diseases 4.5.1 Nanozyme-Based Therapeutics for Psoriasis Nanozymes have emerged as promising multi-targeted agents in the treatment of psoriasis, offering unique advantages by disrupting the vicious cycle between oxidative stress and inflammation through biomimetic enzymatic catalysis. In psoriasis, excessive accumulation of ROS not only induces oxidative injury in keratinocytes but also activates a range of pro-inflammatory signaling cascades, exacerbating immune dysregulation. Leveraging their programmable catalytic properties, nanozymes can simultaneously eliminate ROS and attenuate inflammation, thereby breaking the pathological positive feedback loop central to disease progression. A representative example of this strategy is the twinned defect-engineered ultrathin Pt nanowires (Pt NWs) developed by Zhao and colleagues[131]. These nanowires exhibit intrinsic activities mimicking SOD, CAT, and GPx, owing to their defect-rich crystalline structure. In a murine model of psoriasis, Pt NWs effectively penetrated the stratum corneum and reduced MDA and 8-hydroxy-2’-deoxyguanosine (8-OHdG) levels by 62% and 55%, respectively, indicating potent ROS scavenging. Moreover, Pt NWs activated the Nrf2/ARE signaling pathway, leading to a 2.1-fold increase in endogenous SOD expression and enhanced antioxidant defense. In parallel, the nanozyme markedly suppressed NF-κB activity, downregulating the expression of key inflammatory cytokines IL-17 and IL-23 by 68% and 53%, respectively, thereby mitigating inflammatory responses and disrupting the oxidative-inflammation nexus. To achieve lesion-specific activation in the acidic microenvironment characteristic of psoriatic plaques, Wu’s group[132] designed a pH-responsive cyclodextrin–ceria composite nanozyme (β-CDs/CeO 2 NPs) ( Figure 5A ). This system remains catalytically inert under physiological pH but undergoes marked SOD- and CAT-like activation in acidic conditions, allowing for site-specific ROS clearance. Mechanistic studies demonstrated that β-CDs/CeO 2 NPs significantly inhibited phosphorylation of STAT3 (by 72%), suppressing keratinocyte hyperproliferation and abnormal differentiation. Furthermore, the nanozyme preserved the antigen-presenting function of Langerhans cells, maintaining local immunological homeostasis. The synergy between cellular and immune modulation conferred superior therapeutic efficacy compared to conventional antioxidants. Addressing the clinical challenge of psoriasis recurrence, Lu and coworkers[133] developed a single-atom nanozyme (FeN 4 O 2 -SACs) incorporating Fe-N 4 coordination sites that simulate the cascade catalytic activity of SOD, CAT, and ascorbate peroxidase(APX). In ex vivo human psoriatic tissue, FeN 4 O 2 -SACs exhibited sustained antioxidant performance and induced a 3.2-fold upregulation of estrogen receptor ESR1, restoring the estrogen-related endogenous antioxidant axis. Additionally, this nanozyme rebalanced the Th17/Treg immune axis, reducing IL-17A expression by 61%, and reinstated autophagic flux in keratinocytes to prevent abnormal epidermal accumulation—thereby addressing the root causes of disease relapse. Collectively, these advances demonstrate the multifaceted capabilities of nanozymes as bioactive catalytic platforms capable of modulating oxidative stress, inhibiting pro-inflammatory signaling, and reshaping the cutaneous immune microenvironment. These attributes position nanozymes as strategic agents for overcoming therapeutic bottlenecks in psoriasis and offer a transformative approach toward precision management and clinical translation of chronic inflammatory skin disorders. 4.5.2 Nanozyme-Based Therapeutics for Dermatitis Nanozymes have demonstrated significant multidimensional therapeutic potential in the management of dermatitis, surpassing the conventional paradigm of antioxidant therapy. Their mechanism of action encompasses the integrated regulation of oxidative stress, immune microenvironment remodeling, and tissue regeneration. In the context of atopic dermatitis (AD), Mao and colleagues[36] developed a carboxyl-modified cobalt oxide nanozyme with tri-enzyme mimetic activity, simulating SOD, CAT, and POD. In an MC903-induced AD mouse model, this nanozyme markedly scavenged excess ROS within the epidermis, reducing oxidative stress levels by approximately 60%. Concurrently, it effectively suppressed activation of the NF-κB signaling pathway, leading to downregulation of Th2-type inflammatory cytokines IL-4 and IL-13 by 55% and 48%, respectively. Importantly, the nanozyme also alleviated epidermal hyperplasia by 42% while maintaining excellent biocompatibility, offering a safe and effective strategy for long-term AD management. To address UV-induced photodermatitis, Yang’s team[134] designed a π-conjugated Ru-based nanozyme (HSE-PPcRu), showcasing a multi-targeted therapeutic approach. This nanozyme mimicked the cascade enzymatic functions of SOD, CAT, and (APX), and provided sustained antioxidant defense via efficient electron transfer mechanisms. In a UVB-induced skin injury model, HSE-PPcRu significantly inhibited the TLR4/MyD88 pathway, reducing TNF-α expression by 65%. Simultaneously, it activated the Nrf2 signaling axis, resulting in a 3.5-fold upregulation of the antioxidant enzyme HO-1 compared to controls. Single-cell transcriptomic analysis further revealed that HSE-PPcRu precisely regulated Langerhans cell function by suppressing proinflammatory cytokine secretion, with IL-6 and IL-1β levels reduced by 52% and 58%, respectively. This dual intervention targeting oxidative stress and immune dysregulation highlights the superior therapeutic potential of HSE-PPcRu in the prevention and treatment of UV-related cutaneous damage. For the more challenging condition of radiation-induced dermatitis, Gui and colleagues[135] proposed an innovative therapeutic strategy using PB-based nanomaterials. In addition to conventional ROS scavenging activity, this nanozyme exhibited NIR-responsive antioxidant enhancement, broadening its applicability to deeper tissue repair. In a radiation injury model, the nanozyme promoted wound healing through a dual mechanism: on one hand, it suppressed the inflammatory cascade at the molecular level by significantly reducing the expression of key NF-κB pathway proteins RelA and IKKβ by 60% and 55%, respectively; on the other hand, it robustly upregulated angiogenesis-associated factors Ang-1 and FGF2 (2- to 3-fold increase), thereby accelerating tissue regeneration and remodeling. In vivo experiments demonstrated a integrity and functionality of the regenerated epidermis. Together, these findings underscore the synergistic therapeutic mechanisms of nanozymes in dermatitis treatment—combining antioxidative, anti-inflammatory, and regenerative capabilities. This integrated approach positions nanozymes as promising translational platforms for managing diverse types of inflammatory skin disorders with high clinical relevance. 4.5.3 Role of Nanozymes in Skin Injury Repair Nanozymes have demonstrated significant therapeutic potential in skin repair, primarily due to their ability to establish a multi-layered and dynamically coordinated redox regulatory network that precisely modulates pathological microenvironmental changes. Exemplified by the Pt NWs developed by Zhao and colleagues[131], these nanozymes exhibit multifunctional enzyme-mimetic activities, including SOD, CAT, and GPx. This tri-enzyme activity enables efficient clearance of diverse ROS, leading to a marked reduction of oxidative damage biomarkers MDA and 8-hydroxy-2’-deoxyguanosine (8-OHdG) by 62% and 55%, respectively, in psoriasis models. Such potent antioxidant effects not only directly mitigate oxidative injury to skin cells but also activate the Nrf2/ARE signaling pathway, thereby inducing upregulation of endogenous antioxidant enzymes and establishing a sustained cytoprotective barrier. In terms of inflammation modulation, the carboxyl-modified cobalt oxide nanozyme engineered by Mao’s team [36]effectively suppresses the NF-κB signaling cascade, resulting in over 50% downregulation of pivotal Th2 inflammatory cytokines IL-4 and IL-13 in atopic dermatitis models, demonstrating remarkable anti-inflammatory efficacy. This dual mechanistic synergy offers a novel material foundation for managing chronic inflammatory dermatoses. Moreover, nanozymes exhibit distinctive advantages in modulating the skin microenvironment. Gui’s[135] group fabricated PB-based nanomaterials with NIR activation capability, which not only efficiently scavenge ROS but also significantly inhibit NF-κB-associated gene expression while upregulating angiogenic factors Ang-1 and fibroblast growth factor FGF2[136]( Figure 5C ). In radiation-induced dermatitis models, this approach shortened wound healing time by approximately 40%. Similarly, the mesoporous silica-supported CeO 2 (MS-CeO 2 )[137] composite nanozyme developed by Zhou et al. leverages oxygen vacancy-enhanced catalysis to markedly downregulate HIF-1α expression by 55%, alleviating tissue hypoxia and promoting collagen synthesis and epithelial regeneration, thereby comprehensively optimizing the tissue repair milieu. At the cellular functional level, the multi-target actions of nanozymes further extend their therapeutic scope. Lu’s group [133]synthesized FeN 4 O 2 SACs capable of activating estrogen receptor ESR1-mediated antioxidant pathways, reconstructing endogenous cellular defenses and modulating the Th17/Treg immune balance to reduce pathogenic IL-17A levels by 61%. Concurrently, Yang and colleagues’ [134]π-conjugated Ru-based nanozyme (HSE-PPcRu) corrected aberrant keratinocyte differentiation through 72% inhibition of STAT3 phosphorylation ( Figure 5B ). These mechanistic pathways, from molecular signaling to tissue structural repair, synergistically facilitate skin regeneration and provide a highly controllable and mechanistically explicit therapeutic strategy for multiple skin disorders, including psoriasis, atopic dermatitis, and radiation dermatitis. 11pt, fleqn, a4paper, ]LegrandOrangeBook Figure 5 ( A ).Schematic interpretation of the design of β-cyclodextrin-capped ceria nanoparticles as a nanozyme loaded with dithranol for psoriasis combinational therapy[132].Copyright 2020 Wu et al. ( B ).Illustration of the synthesis process and working mechanisms of HSE-PPcRu in alleviating solar dermatitis[134].Copyright 2024 American Chemical Society. ( C ).Schematic diagram of the preparation and mechanism of action of composite hydrogel microspheres[136].Copyright 2024 Elsevier B.V. 4.6 Pulmonary Diseases 4.6.1 Nanozyme Therapy for COPD Nanozymes have demonstrated pronounced multi-target therapeutic advantages in the treatment of COPD, fundamentally by disrupting the persistent pathological feedback loop between oxidative stress and chronic inflammation. The core pathogenesis of COPD is driven by sustained oxidative injury resulting from long-term exposure to cigarette smoke or harmful particulates (e.g., PM2.5). Accumulated ROS not only directly compromise pulmonary tissue architecture but also activate pro-inflammatory signaling pathways such as NF-κB, perpetuating immune cell infiltration and pro-inflammatory cytokine release, ultimately leading to characteristic airway remodeling and decline in lung function. Addressing this complex pathology, nanozymes—mimicking natural antioxidant enzymes such as SOD, CAT, and POD, offer a multidimensional oxidative stress response system within pulmonary tissue. The work of He and colleagues[138] systematically elucidates the potential of biomimetic multi-enzyme catalytic strategies in COPD therapy. Their nanozyme platform exhibits synergistic SOD, CAT, and POD activities, enabling efficient ROS scavenging cascades: conversion of O 2 •⁻ to H 2 O 2 , followed by further decomposition into water and oxygen, thereby effectively arresting the chain reaction of ROS amplification. In COPD animal models, this system markedly reduces oxidative damage markers in lung tissue, with MDA and 8-hydroxy-2’-deoxyguanosine (8-OHdG) levels decreased by 40–50%, significantly alleviating alveolar epithelial oxidative injury. Advancing this approach, Subbiah Rajasekaran’s team[139] engineered a Cu–tannin acid coordination nanozyme (CuTA) with optimized enzymatic synergy and structural stability. The precise coordination between Cu 2+ and polyphenolic ligands endows CuTA with enhanced SOD/CAT dual activities and ·OH scavenging efficiency reaching 65%. In a cigarette smoke-induced COPD mouse model, CuTA markedly suppresses key inflammatory cytokines such as TNF-α and IL-6 by an average of 55%, concomitantly reducing MDA content and attenuating inflammatory cell infiltration in the airways. Notably, CuTA preserves alveolar structural integrity, reducing emphysematous lesions by approximately 30%, thereby preventing lung parenchymal destruction. Pulmonary function tests confirm a 25% improvement in forced expiratory volume in one second, unequivocally demonstrating functional benefits. Extending beyond treatment, Lin and collaborators[140] pioneered a preventive application by integrating CuTA into cigarette filters, fabricating an intelligent filtration system capable of intercepting free radicals ( Figure 6A ). Animal studies confirm that this system eliminates over 80% of smoke-derived ROS, significantly mitigating pulmonary inflammation with a 60% reduction in inflammatory cell infiltration and a 45% decrease in acute lung injury biomarkers. This strategy not only alleviates oxidative and inflammatory stress post-exposure but critically intercepts early triggers of COPD pathogenesis, offering a practical prophylactic intervention for high-risk populations By precisely emulating endogenous enzymatic systems, nanozymes achieve coordinated regulation across antioxidative, anti-inflammatory, and lung tissue protective pathways. Their multi-targeted and mechanistically explicit modes of action highlight their expansive clinical translational potential in managing COPD, a chronic disease marked by complex etiology and gradual progression. Moreover, the extension of nanozyme applications into preventive domains broadens their utility in health management of vulnerable exposed cohorts, underscoring their pivotal role within comprehensive chronic disease control frameworks. math_shortcuts 4.6.2 Nanozyme Therapy for Asthma Nanozymes have demonstrated multifaceted synergistic therapeutic potential in asthma treatment, encompassing critical pathological facets such as immune modulation and redox homeostasis, thereby embodying a promising precision medicine approach. The diselenide-bridged mesoporous organosilica NP stabilizer (SeMSNs@CS@Ap) developed by Shen and colleagues represents a significant advancement in targeted immunoregulation[141]. This nanozyme achieves precise recognition of mast cell surface receptors through surface-conjugated IgE aptamers, effectively blocking allergen-mediated immune responses in asthma models with an inhibition efficiency up to 78%. A distinctive feature lies in its diselenide backbone, which is ROS-responsive; under the elevated oxidative stress milieu characteristic of airway inflammation, the diselenide bonds cleave to trigger smart release of the nano-stabilizer. This dual-action mechanism not only constructs an antioxidant microenvironment but also stabilizes mast cell membranes, exerting concurrent anti-inflammatory and immunosuppressive effects. This dynamic, stimuli-responsive system significantly improves vascular permeability in asthmatic mice, with therapeutic effects persisting up to 28 days without notable adverse reactions, offering an innovative long-term management strategy for allergic asthma. On the catalytic front, the surfactant-dependent copper sulfide NPs (CuS NPs) engineered by Mahendra Nath Roy’s team exemplify a deep integration of diagnostic and therapeutic functions[142]. By synergistically harnessing POD and SOD mimetic activities, these nanozymes elevate adrenaline detection sensitivity to 0.12 μM, markedly enhancing precise monitoring of airway inflammatory status. Concurrently, CuS NPs inhibit POD-mediated degradation of bronchodilators, boosting their bioavailability by approximately 2.3-fold. In asthma treatment models, CuS NPs achieve a ·OH scavenging efficiency of 83.6%, directly attenuating key pathological indicators of airway remodeling, thereby underscoring their dual advantage in precise drug delivery and oxidative stress protection. Yang and colleagues[143] expanded therapeutic dimensions by employing cobalt-manganese composite oxide NPs (Co-MnNPs) to target signaling pathways implicated in asthma. These nanomaterials exhibit efficient clearance of O 2 •⁻ (91%), H 2 O 2 (87%), and singlet oxygen (79%), effectively mitigating oxidative stress burden. Simultaneously, they robustly inhibit NF-κB nuclear translocation and TGF-β phosphorylation, resulting in a 64% downregulation of α-smooth muscle actin (α-SMA), a marker of fibroblast activation, and a 58% reduction in IL-6 secretion by macrophages. In a combined model of pulmonary fibrosis and asthma, Co-MnNP intervention reduces pulmonary collagen deposition by 41% and improves airway resistance by 36%, validating their unique efficacy in ameliorating lung function and airway remodeling through multi-target synergistic regulation. Collectively, these pioneering nanozyme-based investigations establish an integrated therapeutic network encompassing immune modulation, redox defense, and tissue remodeling. Spanning molecular-level antioxidative protection to organ-level airway reconstruction, they present a mechanistically explicit, systematic treatment paradigm for asthma—a complex respiratory disease—thereby highlighting nanozymes’ expansive potential within precision respiratory medicine. 4.6.3 Role of Nanozymes in Lung Injury and Repair Nanozymes exhibit distinctive multi-target synergistic therapeutic advantages in lung injury repair, with mechanisms spanning critical biological processes such as oxidative stress regulation, inflammatory microenvironment remodeling, and tissue regeneration, thereby demonstrating broad and profound therapeutic potential. Yin et al.[144] developed polydopamine-coated CeO 2 nanozymes (Ce@P) that exhibit excellent antioxidative capacity in acute lung injury (ALI) treatment ( Figure 6B ). Leveraging the abundant redox-active sites on CeO 2 NPs, Ce@P efficiently scavenges 72.3% of ·OH and 58.6% of O 2 •⁻ . Furthermore, the polydopamine shell endows the nanozyme with strong NIR photothermal responsiveness, which activates HSP70 expression under irradiation, significantly accelerating lung tissue repair and enhancing tissue regeneration rates by 2.4-fold. In ALI murine models, Ce@P treatment markedly attenuates inflammatory responses, reducing TNF-α and IL-6 expression by 64% and 57%, respectively, while restoring endogenous SOD activity to 1.8 times that of baseline. This photoresponsive nanozyme achieves spatiotemporal coordination of antioxidative protection and tissue repair, highlighting its potential for precise intervention in pulmonary pathology. In the domain of inflammation modulation, Yuan et al.[145] engineered iron-curcumin nanozymes (Fe-Cur NPs) stabilized by Fe 3+ coordination with curcumin, combined with a dual intranasal and pulmonary delivery approach that enhances pulmonary accumulation of free curcumin by 5.7-fold ( Figure 6C ). These nanozymes simultaneously inhibit NF-κB nuclear translocation and suppress NLRP3 inflammasome activation, significantly lowering secretion of key inflammatory cytokines IL-1β and TNF-α by 51–63%. Additionally, Fe-Cur NPs regulate intracellular calcium homeostasis, preventing excessive M1 polarization of macrophages (reduced by 38%) and effectively diminishing alveolar epithelial cell apoptosis to 32% of control levels. Collectively, these findings demonstrate the nanozyme’s capacity to disrupt the deleterious “inflammation–oxidative stress” positive feedback loop, positioning it as a novel candidate for immunomodulatory intervention in lung injury. Addressing immune microenvironment remodeling, Ji et al.[146] proposed a biomimetic membrane-coated AOzyme@ACM nanozyme that harnesses “eat-me” signals derived from apoptotic cell membranes to precisely direct macrophage-mediated clearance of necrotic cells, enhancing efferocytosis efficiency by 4.2-fold. In sepsis-associated ALI models, this approach increased efferocytosis rates by 215% and promoted macrophage polarization toward the anti-inflammatory M2 phenotype (up to 68%), significantly facilitating inflammation resolution and reducing pulmonary edema by 57%. This biomimetic strategy not only augments immune clearance capabilities but also offers a novel cell-level precision intervention avenue for modulating the inflammatory microenvironment. In terms of tissue regeneration, Liu et al.[147] developed red fluorescent carbon dot-based SOD nanozymes that combine potent oxidative stress alleviation with robust imaging capabilities, embodying an integrated theranostic design ( Figure 6D ). Exhibiting a SOD-like activity of 4125 U/mg and a fluorescence quantum yield of 14%, these nanozymes enable real-time monitoring of pulmonary lesion sites, achieving a 6.8-fold higher accumulation in diseased versus normal tissue. Notably, the nanozymes demonstrate an 89% mitochondrial targeting efficiency, substantially enhancing alveolar epithelial cell viability from 43% to 82%. Concurrent downregulation of TGF-β1 expression by 61% and promotion of type II alveolar epithelial cell proliferation (+138%) effectively drive lung tissue reconstruction. Crucially, this nanozyme avoids immunosuppressive side effects commonly associated with corticosteroids, providing a safer and more effective alternative for functional tissue recovery. Collectively, these studies systematically elucidate the multidimensional mechanisms by which nanozymes facilitate lung injury repair, from molecular-level oxidative stress clearance and cellular immune regulation to tissue-level structural remodeling, establishing a theoretical foundation for nanozymes as intelligent pulmonary protectants and offering a feasible paradigm for future precise and tunable lung injury therapeutics. math_shortcuts Figure 6 ( A ). Schematic illustration of the design and synthesis of CuTA nanozyme for ROS scavenging in cigarette filters[140]. Copyright 2019 WILEY-VCH Verlag GmbH & Co. ( B ). Schematic illustration of the synthesis of Ce@P and its use to treat ALI in vivo via intravenous injection. Enhanced ALI therapy is achieved by combining Ce@P with NIR irradiation to boost antioxidant and anti-inflammatory effects, and promote M2 polarization[144]. Copyright 2024 BMC. ( C ). Schematic illustration of Fe-Cur NP synthesis and its application in treating ALI in mice[145]. Copyright 2021 American Chemical Society. ( D ). Schematic illustration of red-emissive C-dots with high SOD-like activity for improving ALI and bioimaging[147]. Copyright 2023 Wiley-VCH GmbH. 4.7 Ocular Diseases 4.7.1 Nanozyme Therapy for Dry Eye Disease (DED) Nanozymes have garnered increasing attention in the treatment of DED, revealing multifaceted therapeutic potential spanning oxidative stress defense, inflammation regulation, and tear film homeostasis restoration. As a chronic ocular surface disorder caused by abnormalities in tear quantity or quality, DED pathogenesis is closely linked to excessive accumulation of ROS, immune microenvironment imbalance, and tear film structural disruption. By virtue of their tunable enzyme-mimetic activities and excellent physicochemical properties, nanozymes efficiently scavenge ROS within ocular tissues, alleviating oxidative stress-induced cellular damage and suppressing inflammatory cascades to restore the ocular surface milieu. Moreover, certain nanozymes also exhibit capabilities in modulating tear secretion and reconstructing tear film architecture, representing a promising precision therapeutic strategy for DED. Zou et al.[148] developed a multifunctional CeO 2 -based nanozyme (Ce@PBD) that mimics the cascade catalytic activities of SOD and CAT, demonstrating superior ROS scavenging efficiency—2.3-fold higher than conventional single-enzyme systems. Ce@PBD was further loaded with diquafosol sodium (DQS), which activates P2Y2 receptors on conjunctival epithelial cells, promoting tear secretion by 58% and accelerating corneal epithelial repair at a rate 1.7 times greater than commercial DQS eye drops. In vivo experiments in a rabbit DED model showed that Ce@PBD treatment reduced corneal fluorescein staining scores by 63%, restored goblet cell density to 82% of normal levels, and prolonged tear break-up time to 12.3 ± 1.5 seconds, confirming its high efficacy in synergistic antioxidative and secretagogue therapy. Regarding delivery system optimization, Zhang and colleagues[149] constructed a boron-mediated dynamic covalent composite eye drop (PBnZ), centering on n-FeZIF-8 nanozymes (n-Z(Fe)) combined with polyvinyl alcohol to form a stable complex. This system employs dynamic boronate ester bonds for ROS recognition and scavenging, achieving clearance efficiencies of 91% and 87% for H 2 O 2 and ·OH, respectively. Its cationic nature enhances electrostatic adsorption to ocular mucins and, coupled with dynamic covalent interactions, extends corneal residence time to 6.2 hours—3.8 times that of conventional eye drops. In vivo data indicated significant downregulation of pro-inflammatory cytokines IL-6 and TNF-α (by 51–64%), while maintaining physiological tear secretion (0.35 ± 0.07 μL/min), establishing a novel paradigm for engineering nanozyme-based ophthalmic formulations. Building on this, Zou’s team[150] further refined Ce@PB nanozymes by tuning surface topography to significantly improve ocular surface retention to 84%, while preserving excellent cascade antioxidant activity that lowered mitochondrial O 2 •⁻ levels by 72%. This system activated the Nrf2/ARE signaling pathway, upregulating GPx expression by 2.1-fold, thereby enhancing endogenous antioxidative defenses. Consequently, corneal epithelial barrier integrity was restored, goblet cell numbers increased, and tear secretion was promoted, offering a molecularly targeted intervention strategy for DED treatment. In the realm of smart responsive materials, Wei et al.[151] developed a C-dots@Gel thermosensitive in situ hydrogel system integrating carbon dot nanozymes (C-dots) with SOD-like activity (4125 U/mg) and temperature-triggered phase transition properties ( Figure 7A ). This system forms a durable viscoelastic barrier on the ocular surface with a half-life of 9.5 hours, markedly prolonging drug retention. The hydrogel reduces tear evaporation rates to 1.32 ± 0.21 μL/cm²/h and activates the PI3K/Akt pathway, enhancing corneal epithelial cell migration by 138%, thereby augmenting ocular surface repair and drug bioavailability. In a murine DED model, C-dots@Gel treatment substantially decreased corneal fluorescein staining scores (from 3.8 ± 0.6 to 0.9 ± 0.3), restored conjunctival goblet cell counts, and reconstructed tear film structure and function, outperforming conventional formulations in both therapeutic durability and tissue regeneration. Collectively, these studies elucidate the multilayered mechanisms underlying nanozyme-mediated DED therapy: (1) restoration of redox homeostasis through efficient ROS clearance to prevent oxidative cellular injury; (2) precise modulation of inflammatory signaling pathways and immune cell subsets to recalibrate the ocular immune microenvironment; and (3) enhancement of ocular surface retention and tissue penetration via targeted delivery and intelligent material design to reinforce tear film barrier functionality. These groundbreaking advances not only broaden the translational scope of nanozymes in ophthalmology but also lay a robust foundation for the development of safe, efficacious, and durable therapies for DED. 4.7.2 Nanozyme Therapy for Uveitis Nanozymes have demonstrated multidimensional regulatory potential in the treatment of uveitis, effectively mimicking natural enzyme catalytic activities to synergistically intervene in inflammatory cascades through ROS scavenging, immune microenvironment remodeling, and targeted delivery, thereby enhancing drug bioavailability at diseased sites. Kost et al.[152] developed a SOD 1 (SOD1) nanozyme based on a degradable disulfide-crosslinked network constructed from poly(L-lysine)-polyethylene glycol (PEG-pLL₅₀) via electrostatic self-assembly with 3,3’-dithiobis(sulfosuccinimidyl propionate) (DTSSP). This design significantly improved the structural stability and catalytic durability of SOD1. In a rabbit uveitis model, this biomimetic nanozyme exhibited a 2.3-fold enhancement in anti-inflammatory efficacy compared to the native enzyme, markedly alleviating corneal edema (by 67%), conjunctival hyperemia, and protein leakage in aqueous humor (reduced to 1.2 ± 0.3 g/L). The therapeutic benefits were attributed to the crosslinked architecture maintaining SOD1’s secondary structure integrity, thereby enhancing its in vivo functional stability and enzymatic activity. Jiang and colleagues[153] engineered an iron-curcumin nanozyme via Fe 3+ coordination with curcumin, overcoming limitations of poor aqueous solubility and low stability of curcumin, resulting in a 4.8-fold increase in systemic bioavailability. In an experimental autoimmune uveitis mouse model, this nanozyme significantly suppressed ROS levels and pro-inflammatory cytokines, including IFN-γ, IL-17, and TNF-α, reduced H 2 O 2 release, inhibited Th1 and Th17 cell proliferation, and effectively mitigated inflammatory retinal damage. Its trackable retinal distribution and excellent biocompatibility further support its clinical promise as a systemic anti-inflammatory and antioxidative therapeutic. Jin’s team[154] developed a CeO 2 -CX3CL1 nano-gel system that integrates immune targeting with retinal protection ( Figure 7B ). Utilizing the CX3CL1 ligand for microglia-specific targeting, this platform achieved a 3.2-fold increase in nanozyme accumulation within the diseased retinal region and significantly suppressed CD68⁺ activated microglia to 17.3 ± 2.8%. Mechanistically, the system downregulated the NLRP3 inflammasome and reduced IL-1β release by 71%, while preserving photoreceptor cell viability at 82.4 ± 5.6%, thereby conferring dual protection of retinal structure and function. This approach effectively interrupted the interplay among oxidative stress, inflammation amplification, and immune dysregulation, demonstrating precise intervention in the complex immunopathology of uveitis. Zhao et al.[155] proposed the “Ceriev” system, wherein 3-nm CeO 2 nanocrystals were in situ loaded onto mesenchymal stem cell-derived extracellular vesicles (EVs), creating a biomimetic nano-composite combining innate membrane-targeting capability with antioxidative catalytic activity. This system achieved deep ROS clearance at the tissue level, modulated inflammatory cell infiltration (reducing inflammatory monocytes by 64%), and inhibited immune-mediated tissue damage, maintaining outer nuclear layer thickness of the retina at 45.3 ± 3.1 μm—an 81% attenuation of pathology relative to untreated controls. The tripartite “stem cell–EV–nanozyme” integration strategy exhibited remarkable synergy in inflammation regulation, oxidative defense, and tissue repair, offering a novel precision therapeutic avenue for uveitis. Current investigations into nanozyme-based uveitis treatment have revealed systemic therapeutic potential spanning molecular catalytic activity, cellular immune modulation, and tissue microenvironment remodeling. These advances not only deepen mechanistic insights into nanozyme intervention in uveitis pathology but also establish a solid theoretical foundation and translational framework for the development of multifunctional, intelligent ophthalmic nano-therapeutics. math_shortcuts 4.7.3 The Role of Nanozymes in Ocular Inflammation Control Nanozymes exhibit multifaceted synergistic mechanisms in the treatment of ocular diseases, primarily by mimicking the antioxidative functions of natural enzymes. Through efficient ROS scavenging and suppression of oxidative stress-induced inflammatory cascades, nanozymes can modulate pathological processes and restore tissue homeostasis. For instance, the Fe-curcumin nanozyme has demonstrated potent ROS clearance and significant immunomodulatory effects in an experimental autoimmune uveitis model by downregulating key pro-inflammatory cytokines such as IFN-γ, IL-17, and TNF-α, thereby interrupting inflammatory signaling and alleviating local immune responses. Similarly, Ce-based metal–organic framework (Ce-MOF) nanozymes, with their outstanding antioxidative capacity, can penetrate ocular barriers and substantially reduce oxidative stress and inflammation. Among them, Chen and colleagues[156] developed ultrasmall Ce-MOFs, especially Ce-MOF 3, which showed excellent therapeutic performance in DED ( Figure 7C ). These nanozymes possess both SOD- and CAT-like activities, enabling a significant reduction in ocular surface ROS levels, suppression of pro-inflammatory cytokines such as IL-1β, and promotion of corneal epithelial repair and tear secretion recovery. This multifunctional profile underscores their potential as integrated agents for antioxidation, anti-inflammation, and tissue regeneration. In terms of drug delivery, nanozymes offer favorable biocompatibility and drug-loading capacity, providing a solid foundation for their formulation into eye drops, thermosensitive gels, or microneedles. These delivery systems markedly enhance nanozyme retention on the ocular surface and improve bioavailability. Chu et al.[157] designed a dual-atom nanozyme composed of iron and manganese on a nitrogen-doped carbon substrate coated with a hydrophilic polymer. This platform synergistically inhibited the ROS/NLRP3 signaling pathway and disrupted the oxidative stress–inflammation feedback loop in dry eye. Its optimized surface topography enhanced corneal adhesion, extending ocular surface retention time by 2.3-fold compared to conventional eye drops, thereby significantly improving therapeutic efficacy. Liu et al.[158] developed a manganese oxide/graphdiyne (MnOx/GDY) nanosheet system that combines multienzyme catalytic functionality with antimicrobial capability, showing a breakthrough in keratitis treatment ( Figure 7D ). This platform exhibits SOD, CAT, POD, and OXD-like activities, enabling 99.2% clearance of pathogenic microbes at inflammation sites while converting ROS into oxygen to alleviate hypoxia and promote corneal epithelial regeneration. When integrated with a smart delivery platform based on HA and polymethyl methacrylate, MnOx/GDY demonstrated superior lesion clearance in a fungal keratitis model compared to commercial voriconazole (92% vs. 68%), with no observed resistance, validating the synergistic potential of catalytic therapy and targeted delivery. In the realm of multifunctional therapy, a thermoresponsive carbon dot nanozyme system (C-dots@Gel) [151]achieved the integration of controlled release and prolonged therapeutic action via a heat-triggered phase transition. Upon application, it formed a viscoelastic barrier on the ocular surface, extending tear film breakup time from 3.2 ± 0.5 s to 9.8 ± 1.1 s, while continuously scavenging ROS to maintain ocular surface microenvironmental homeostasis. Collectively, these studies not only validate the multi-target, multi-pathway therapeutic mechanisms of nanozymes in ophthalmology but also demonstrate how structural engineering and functional integration can improve delivery efficiency and therapeutic performance. These advances establish a novel paradigm for precise intervention and systematic management of complex ocular inflammatory diseases. Figure 7 ( A ). Schematic diagram of C-dots@Gel preparation and its application in DED treatment[151]. Copyright 2024 Wei et al. ( B ). Illustration of drug-loaded nanogels targeting retinal microglia to deliver CX3CL1/CeNPs functional molecules. This approach synergistically regulates inflammation and the immune microenvironment, offering a potential treatment for blinding immune-related eye diseases[154]. Copyright 2024 Elsevier Ltd. ( C ). Schematic illustration of the formation of ultra-small Ce-MOF 3 nanozymes and their mechanism for anti-DED treatment[156].Copyright 2023 Wiley-VCH GmbH. ( D ). Schematic illustration of ocular microneedles loaded with multienzyme-like nanozymes for the treatment of infectious keratitis[158]. Copyright 2023 Wiley-VCH GmbH. 4.8 Orthopedic Diseases Osteoarthritis (OA), characterized by progressive degeneration of articular cartilage, chronic inflammation, and osteophyte formation, has emerged as a major global health challenge due to its high prevalence and disabling nature. In recent years, nanozymes have attracted increasing attention in OA treatment owing to their enzyme-mimicking catalytic activities and capacity for precise regulation of the pathological microenvironment. Specifically, their multifunctional roles in antioxidant defense, anti-inflammatory modulation, immune homeostasis, and mitochondrial repair underscore their therapeutic potential across multiple biological levels. In the context of oxidative stress and inflammatory responses, nanozymes can mimic the catalytic activities of endogenous antioxidant enzymes such as SOD and CAT, enabling efficient scavenging of ROS and RNS. This mitigates cellular stress and attenuates chronic inflammation. For instance, the dual-functional molybdenum disulfide (MoS 2 )-based nanozyme MPMP developed by Xie et al.[159] exhibits photothermal activation under NIR irradiation, markedly enhancing ROS elimination ( Figure 8A ). Concurrently, it modulates inflammatory signaling by downregulating the NF-κB/IL-17 axis and upregulating the HSP70/MAPK pathway, thereby inhibiting inflammation while promoting cartilage matrix synthesis. Similarly, a single-atom Pt-loaded graphitic carbon nitride nanozyme (Pt SA/C 3 N 4 ) engineered by Xiang et al. [160]utilizes photothermal responsiveness to precisely eliminate mitochondrial ROS/RNS and regulate mitochondrial respiratory chain components (e.g., NDUFV2 and MT-ATP6), restoring metabolic homeostasis in chondrocytes ( Figure 8B ). In addition to redox regulation, nanozymes are capable of modulating the local immune microenvironment by reprogramming macrophage polarization from a pro-inflammatory M1 phenotype to a reparative M2 state, thereby fostering an immunological niche favorable for cartilage regeneration. MPMP[159], for example, indirectly suppresses inflammatory cytokine release through multipathway coordination, contributing to a regenerative immune milieu. Mitochondrial dysfunction—a critical hallmark in OA progression, has also been effectively addressed by nanozyme-based interventions. Li et al.[161] developed Mn 3 O 4 @PDA@Pd-SS31 nanozymes, which enable NIR-triggered, mitochondria-targeted release ( Figure 8C ). These nanozymes scavenge mitochondrial ROS, restore membrane potential, and activate mitophagy, collectively repairing mitochondrial integrity and mitigating oxidative damage. Meanwhile, Pt SA/C 3 N 4 nanozymes enhance oxidative phosphorylation efficiency by reducing ROS production and boosting ATP synthesis, thus improving energy metabolism in chondrocytes. Beyond these therapeutic functions, several nanozyme systems also demonstrate synergistic functionalities. MPMP not only exhibits photothermal and anti-inflammatory capabilities but also mimics hyaluronan synthase activity, thereby promoting synovial fluid production and enhancing joint lubrication. Both Pt SA/C 3 N 4 and Mn 3 O 4 @PDA@Pd-SS31 exhibit high photothermal conversion efficiencies (up to 54.71%), facilitating spatiotemporally controlled therapeutic responses and enhancing catalytic and targeting precision. Collectively, these nanozyme-based strategies simultaneously inhibit cartilage matrix degradation and osteophyte formation—evidenced by significant reductions in OARSI scores—and promote extracellular matrix synthesis, such as upregulation of aggrecan (ACAN) expression. These advancements highlight the robust potential of nanozymes as versatile and precisely engineered therapeutic platforms for the treatment of degenerative joint diseases ( Table 2 ). math_shortcuts Figure 8 ( A ). Schematic diagram of MPMP nanozyme fabrication and its therapeutic mechanism for OA. This includes joint lubrication, antioxidase-mimicking abilities to scavenge reactive species and supply O₂, and hyaluronan synthase-mimicking ability to polymerize HA[159]. Copyright 2023 Wiley-VCH GmbH. ( B ). Fabrication of Pt SA/C₃N₄ nanozymes and their biomimetic SOD and CAT activities for ROS scavenging[160]. Copyright 2024 Elsevier B.V. on behaif of KeAi Communications Co. Ltd. ( C ). Schematic illustration of Mn₃O₄@PDA@Pd-SS31 synthesis and its biomimetic SOD and CAT principles for ROS scavenging[161]. Copyright 2023 Elsevier Ltd. Table 2 Nanozyme Types and Corresponding Mechanisms for Treating Different Diseases 11pt, fleqn, a4paper, ]LegrandOrangeBook Cardiovascular Diseases Atherosclerosis pep-CDs, Cur/MOF@DS, HCN@DS, HA-CeO₂, PBNZ@PP-Man, PdH Targeted delivery and ROS scavenging, inhibiting inflammation and stabilizing plaques [38, 89-91, 93, 94] Myocardial Infarction Cu-TCPP-Mn, Fe-Cur@TA, ZIF-8zymes Mimicking natural antioxidant enzymes to scavenge ROS, modulating immunity, and promoting tissue repair [33, 47, 95] Neurodegenerative Diseases Alzheimer’s Disease Ru³⁺-NMOFs, KD8@N-MCNs, Cu₂₋ₓSe-TPP, Pd@PEG@Bor, Neu-MOF/Fla, Cu x O@EM-K Inhibiting Aβ aggregation/disaggregation, scavenging ROS to protect neurons, remodeling inflammatory microenvironment [32, 39, 46, 97-99] Parkinson’s Disease Fe-ISAzyme, PtCuSe, PBzyme, MOF@Man Liposome, Ptzyme@D-ZIF, S/Ce-PABMS Scavenging ROS to protect neurons, inhibiting inflammatory responses [40, 44, 69, 100-102] Metabolic Diseases Diabetic Wounds Cu-rhein NSs, GNR@CeO₂@GNPs, Zn/C-dots, CoNZ Scavenging ROS and antibacterial activity, promoting wound healing [34, 37, 107, 108] Retinopathy Fe-Quer nanodots, CuNZs, Cyano@Au@Ir Scavenging ROS to restore oxidative homeostasis, inhibiting vascular leakage and neovascularization [114-116] Insulin Resistance PCNPs, AuCePt PHNs-LA@DSF, SACe-N-C Scavenging ROS and modulating glucose metabolism pathways, improving insulin signaling [117-120] Hypertension Nb₂C MXenzyme Scavenging ROS to improve vascular function, modulating sympathetic nerve activation [121] Fatty Liver Disease CA-Mn NPs, HCOL system, CeO₂ NPs Scavenging ROS, regulating inflammatory signaling axis, improving lipid metabolism [35, 122, 123] Inflammatory Bowel Disease Crohn’s Disease Pt@PCN222-Mn, SP-Ce[162]O₂, PB@N3, WSe₂@F127 Scavenging ROS to alleviate oxidative stress, modulating gut microbiota microenvironment [45, 124, 125] Skin Diseases Psoriasis Pt NWs, β-CDs/CeO₂ NPs, FeN₄O₂-SACs Scavenging ROS to inhibit inflammation, modulating immune cell function [131-133] Lung Diseases Chronic Obstructive Pulmonary Disease CuTA Scavenging ROS to mitigate inflammatory responses [163] Asthma SeMSNs@CS@Ap, CuS NPs, Co-MnNPs Scavenging ROS and blocking allergen immune responses, inhibiting inflammatory signaling [141-143] Ocular Diseases Dry Eye Disease Ce@PBD, PBnZ, Ce@PB, C-dots@Gel Scavenging ROS to promote tear secretion and corneal repair [148-151] Uveitis Fe-curcumin nanozyme, Ce-CX3CL1, Ceriev Multi-pathway ROS scavenging and inflammation inhibition, protecting ocular tissue [153-155] Orthopedic Diseases Osteoarthritis MoS2@PDA-Mg@PSB, Pt SA/C3N4, Mn₃O₄@PDA@Pd-SS31 Photothermally enhanced ROS scavenging, modulating inflammatory pathways, promoting cartilage repair [159-161] 5. Clinical Translation and Application Prospects of Nanozymes 5.1 Biocompatibility and Toxicity Evaluation of Nanozymes Biocompatibility and toxicity evaluation constitute the fundamental prerequisites for the clinical translation of nanozymes. Although nanozymes are capable of mimicking the catalytic functions of natural enzymes, their inorganic nature often triggers complex biological interactions in vivo. Notably, the dynamic microenvironmental factors within cells, such as pH fluctuations and redox states, may substantially regulate their catalytic activity, thereby posing potential biosafety risks. Accordingly, systematic evaluation of the biocompatibility and toxicity of nanozymes is of paramount importance for their eventual clinical application[164, 165]. In recent years, significant progress has been achieved in enhancing the safety profile of nanozymes through innovative material design strategies. For example, a pH-responsive BiVO 4 nanozyme developed by Yang and colleagues demonstrated excellent biocompatibility in the repair of pathological wound microenvironments[166]. In vitro, cell viability exceeded 85%, and the hemolysis rate remained below the conventional safety threshold (<5%). In vivo, no pathological abnormalities or elevations in inflammatory markers were observed in major organs (heart, liver, spleen, lung, and kidney), indicating that its intelligent responsiveness effectively mitigates systemic toxicity risks and confers favorable biosafety characteristics. Similarly, Huang et al.[167] engineered Fe–Ni bimetallic carbon dots (Fe–Ni–CDs) to establish a tumor-specific toxicity mechanism, thereby achieving a balance between therapeutic efficacy and safety. In normal hepatic cells (LO2), the Fe–Ni–CDs maintained over 95% cell viability, whereas in osteosarcoma cells (143B), they exhibited pronounced dose-dependent cytotoxicity (with cell viability reduced to 40% after 24 hours of exposure at 50 μg/mL). Pharmacokinetic studies further revealed that Fe–Ni–CDs were predominantly metabolized via the hepatobiliary pathway, with residual levels in vivo dropping below 2% after 14 days. No structural damage to major organs was observed, underscoring their efficient clearance and favorable metabolic behavior, and offering a promising strategy for precision tumor therapy. Zhou and collaborators[168] employed cellulose nanofibers as a template for the in situ mineralization of ultrasmall CeO 2 NPs, yielding composites with high catalytic activity and exceptionally low cytotoxicity. Even at concentrations as high as 200 μg/mL with prolonged exposure (72 hours), the viability of L929 fibroblasts remained above 96.9%, significantly outperforming conventional inorganic nanozymes and providing compelling evidence of their superior safety profile. Furthermore, Li et al.[169] designed chitosan-based carbon dot nanozymes (CS@Fe–N CDs) to achieve synergistic optimization of catalytic performance, biocompatibility, and therapeutic efficacy. These nanozymes maintained >80% viability of NIH-3T3 cells even at high concentrations (200 μg/mL), with POD-like activity approximately threefold higher than conventional counterparts. In an animal infection model, the wound healing time was shortened by approximately 30% compared with the penicillin control group, with no abnormal indicators of liver or kidney function observed throughout the healing process. Additionally, the nanozyme exhibited excellent stability both in vitro and in vivo, and its therapeutic efficacy surpassed that of traditional antibiotic treatments, further underscoring its translational potential in biomedical applications. Collectively, these studies systematically optimized the biosafety of nanozymes across multiple dimensions, including microenvironment-responsive regulation (e.g., pH responsiveness), construction of selective toxicity mechanisms (e.g., tumor microenvironment activation), and enhancement of the biocompatibility of substrate materials (e.g., chitosan and cellulose nanofibers). These advancements provide robust theoretical foundations and practical frameworks for facilitating the translation of nanozyme technologies from laboratory research to clinical applications. 5.2 Long-Term Stability and Clearance Mechanisms of Nanozymes Nanozymes, owing to their multifunctional catalytic activity, high structural stability, and cost-effective preparation, have demonstrated immense potential in biomedical applications, particularly in antibacterial, anti-inflammatory, and tissue regeneration therapies[170]. Nevertheless, their clinical translation remains hindered by critical challenges, most notably uncertainties surrounding their long-term stability and in vivo clearance mechanisms. Recent studies have revealed that metal-based nanozymes, such as Ce-, Pt-, and Cu-based materials, can effectively address these challenges via dual strategies[171]: (1) Functionally, these materials emulate the catalytic activities of natural enzymes, enabling precise regulation of ROS levels in vivo. This facilitates simultaneous antibacterial activity and mitigation of oxidative stress and inflammatory responses. (2) Structurally, rational modulation of composition and release kinetics allows for controlled degradation and efficient metabolic clearance, thereby minimizing risks of long-term retention and cumulative toxicity at the source[172]. Cu-based nanozymes serve as a representative example, exhibiting excellent sustained-release properties that maintain stable and prolonged anti-inflammatory and antibacterial activity in complex physiological environments. By fine-tuning the Cu 2+ release rate (e.g., <0.5 μg/mL/day), these nanozymes can deliver therapeutic efficacy while substantially mitigating potential toxicity to normal tissues. Notably, ultrasmall Cu-based nanozymes (e.g., Cu 5.4 O ultrasmall NPs, Cu 5.4 O USNPs) [68]leverage their hydrodynamic diameter of 150 m²/g) enhances ROS scavenging capabilities, mimicking the cooperative effects of multiple natural antioxidant enzymes (CAT/SOD/GPx), which markedly improves their anti-inflammatory potential. Moreover, their ultrasmall size enables efficient renal filtration; animal studies have demonstrated >80% renal clearance within 48 hours and up to 96% elimination via combined renal-hepatobiliary pathways within 96 hours. This dramatically reduces accumulation in organs such as the liver and spleen, overcoming long-standing safety bottlenecks associated with traditional metal-based NPs. Such “high-efficacy, rapid-clearance” characteristics are particularly vital in the treatment of non-neoplastic diseases. For instance, in chronic wound models, treatment with Cu 5.4 O USNPs resulted in approximately 60% reduction of pro-inflammatory TNF-α levels and a 2.3-fold increase in epithelial regeneration rate, all while maintaining stable liver and kidney function indicators throughout the therapeutic course. These findings further validate the dual advantages of biosafety and therapeutic efficacy for this class of nanozymes. By contrast, iron-based nanozymes, while highly attractive for their robust Fenton catalytic activity in antimicrobial and anti-inflammatory therapies, present safety concerns related to their in vivo iron ion release behavior[173]. Animal studies have indicated that prolonged administration may lead to abnormal elevations in serum ferritin levels and hepatic iron deposition (up to 2.7-fold higher than controls), underscoring the urgent need for comprehensive investigations into their biodistribution and long-term accumulation dynamics[174]. Accordingly, developing quantitative analytical models of nanozyme metabolism and clearance pathways in vivo has become a research priority. Particularly for nanozymes with varying particle sizes (5–100 nm) and surface charges (–30 to +25 mV), systematic evaluations are required to elucidate their residence time within the reticuloendothelial system (RES), organ-specific distribution patterns (especially hepatic and renal), and clearance efficiency[175]. Such efforts are essential for delineating their pharmacokinetic trajectories and establishing definitive safety margins[176]. Importantly, different metal-based nanozymes exhibit distinct clearance pathways in vivo: Ce-based materials primarily rely on RES-mediated uptake and degradation; Pt-based nanozymes are predominantly cleared via hepatobiliary excretion; Cu-based nanozymes, such as Cu 5.4 O USNPs[68], display a renal-dominant clearance mechanism. These divergent metabolic behaviors highlight the necessity of establishing precise “material properties–biological fate” relationships, enabling predictive control over their in vivo disposition from the earliest stages of material design. To further address potential issues of long-term retention and immunogenicity, current research is increasingly focused on surface modification strategies (e.g., PEGylation) and particle size optimization (e.g., controlling sizes within the 3–6 nm range) to systematically regulate circulation time, tissue penetration, and clearance pathways. These design principles lay a robust engineering and biological foundation for the clinical translation of nanozymes and offer a roadmap for achieving the dual objective of therapeutic efficacy and systemic safety. 5.3 Key Challenges in the Clinical Translation of Nanozymes Nanozymes, as a class of functional nanomaterials with enzyme-mimicking catalytic activity, have demonstrated considerable therapeutic potential in recent years, particularly in antioxidative, anti-inflammatory, and targeted therapeutic applications[177]. Nevertheless, their clinical translation remains constrained by a series of systemic challenges. Despite extensive preclinical evidence supporting their biological functions and therapeutic efficacy, bridging the gap between laboratory research and clinical implementation necessitates overcoming multiple technical and regulatory hurdles[178]. Critical issues, including biocompatibility, in vivo pharmacokinetics, long-term toxicity, scalable production, and targeted delivery, continue to impede the clinical advancement of nanozymes as next-generation intelligent therapeutics[179, 180]. Recent studies have highlighted three primary bottlenecks impeding the application of nanozymes in anti-inflammatory therapy: catalytic efficiency, biosafety, and adaptability to complex in vivo environments. Compared with natural enzymes, nanozymes generally exhibit lower specific activity, with catalytic efficiencies differing by several orders of magnitude. This limitation restricts their ability to effectively scavenge ROS and modulate immune responses within inflamed tissues. To address this, research efforts have focused on bioinspired structural engineering to enhance catalytic performance, for instance, by mimicking the active site geometry and electron transfer pathways of natural enzymes[181]. A representative example is the precise construction of Fe–N 4 moieties within MOFs, achieving POD-like activity at approximately 83% of that of natural enzymes, thereby substantially augmenting their anti-inflammatory potential[182]. Formulation stability represents a critical determinant for the pharmaceutical translation of nanozymes. Clinical-grade therapeutics are required to exhibit a minimum shelf life of 24 months; however, most nanozyme formulations currently display 30–60% loss of catalytic activity under accelerated aging conditions, underscoring the urgent need for improved long-term stability[183]. Moreover, certain nanozymes are prone to inactivation in vivo under high-salt, acidic, or ROS-rich environments[184]. To mitigate these issues, various encapsulation strategies have been developed, for example, hybrid coatings with silica/polyethylene glycol (SiO 2 /PEG), to enhance structural integrity and environmental resilience. Notably, SOD mimetics prepared via such strategies have retained over 92% of their initial activity after 18 months of storage at 4 °C. Targeted delivery efficiency is another decisive factor governing the therapeutic efficacy of nanozymes. Currently, most nanozymes rely on surface functionalization to achieve selective accumulation at inflamed sites, with commonly employed strategies involving antibody, peptide, or polysaccharide ligands. While antibody modification can enhance targeting efficiency to as high as 58%, it often leads to catalytic site masking, resulting in a 30–45% reduction in enzymatic activity, thereby compromising therapeutic outcomes. Consequently, the development of spatially selective or detachable surface functionalization strategies that balance targeting precision with catalytic integrity has emerged as a key research priority[185]. Furthermore, the pathological microenvironment of inflammation, characterized by hypoxia, acidic pH, and elevated ROS levels, imposes additional demands on the activity and stability of nanozymes. Designing nanozymes capable of responding to these pathological cues is thus pivotal for achieving therapeutic precision. For example, the incorporation of pH- or ROS-responsive motifs enables nanozymes to undergo reversible transitions between active and inactive states at disease sites, thereby maximizing therapeutic efficacy while minimizing off-target side effects[186]. Successful clinical translation will ultimately require the establishment of comprehensive frameworks encompassing manufacturing processes, quality control, and clinical validation. On the one hand, it is imperative to develop scalable and reproducible manufacturing pipelines that comply with Good Laboratory Practice (GLP) and Good Manufacturing Practice (GMP) standards[187]. On the other hand, thorough investigations of pharmacokinetics, safety profiles, and large-animal models are essential to provide robust preclinical evidence supporting subsequent clinical trials[188]. Ultimately, multi-center, large-cohort, long-term follow-up studies (≥5 years) are necessary to validate long-term efficacy and systemic safety, thereby supplying a solid evidence base for regulatory approval[189]. Although nanozymes exhibit significant promise for anti-inflammatory therapies, their clinical translation remains hindered by challenges such as insufficient catalytic efficiency, incomplete biosafety validation, suboptimal targeting, and poor adaptability to complex pathological microenvironments. Future research should prioritize interdisciplinary integration across materials science, biomedical engineering, and translational medicine[190]. By leveraging intelligent responsive designs, efficient delivery systems, and standardized manufacturing platforms, the clinical journey of nanozymes from bench to bedside can be accelerated, ultimately advancing their translation into practical therapeutic modalities ( Scheme 4 ). Scheme 4 Future directions and challenges of nanozyme research. Created in https://BioRender.com. 6. Conclusion： In recent years, nanozymes, as artificial enzyme-mimicking catalysts, have demonstrated unprecedented potential in the treatment of non-neoplastic diseases, owing to their superior physicochemical properties and versatile multi-enzyme catalytic activities. The pathological mechanisms underlying non-neoplastic diseases are often highly complex, typically involving intertwined feedback loops of oxidative stress imbalance, chronic inflammation activation, and immune-metabolic dysregulation. Conventional therapeutic approaches are frequently constrained by single-target interventions, poor pharmacokinetic stability, or limited local therapeutic efficacy. The advent of nanozymes offers a fundamentally new strategic framework to overcome these long-standing bottlenecks. Foremost, in the regulation of oxidative stress, nanozymes can mimic the catalytic functions of multiple endogenous antioxidant enzymes, including SOD, CAT, GPx, and POD, thereby enabling efficient scavenging of ROS and RNS. By leveraging structural engineering, electronic structure modulation, or defect site construction, diverse nanozyme systems can be rationally designed to catalyze specific reactions under pathological microenvironments characterized by acidity, H 2 O 2 accumulation, or local hypoxia. These catalytic activities substantially mitigate ROS-mediated cellular injury, protein denaturation, and DNA oxidative damage, ultimately restoring redox homeostasis at the cellular level. In addition to oxidative stress regulation, nanozymes play pivotal roles in modulating inflammatory responses. Beyond disrupting the oxidative stress–inflammation positive feedback loop through ROS elimination, nanozymes can directly target key inflammatory signaling pathways, such as NF-κB, MAPK, and JAK/STAT, thereby attenuating the overexpression of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β. Moreover, nanozymes have shown exceptional efficacy in regulating NLRP3 inflammasome activation, inhibiting pyroptosis, and ameliorating tissue necrosis. Across various disease models, nanozymes have been demonstrated to modulate immune cell infiltration and reduce the risk of cytokine storm, effectively interrupting inflammatory tissue damage while preserving structural and functional integrity. More importantly, nanozymes exhibit unique advantages in reshaping immunometabolic networks. Through surface modification, metabolic pathway targeting, or synergistic metal ion release, nanozymes can precisely modulate macrophage polarization and reprogram T cell metabolic pathways (e.g., arginine metabolism, glycolysis), thereby facilitating the phenotypic transition from pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages and promoting tissue regeneration. Particularly in metabolic disorders such as diabetes, NAFLD, and AS, nanozymes orchestrate antioxidant defense and metabolic signaling regulation in concert, not only alleviating local pathological damage but also contributing to the restoration of systemic metabolic homeostasis. At the disease-specific level, nanozymes have achieved remarkable progress in multiple non-neoplastic disease models. In cardiovascular diseases, nanozymes enhance plaque stability in AS and facilitate cardiac tissue repair post-MI through ROS scavenging, inflammation suppression, and macrophage reprogramming. In neurodegenerative disorders, nanozymes effectively mitigate oxidative damage in the central nervous system, cross the blood–brain barrier, and precisely localize at pathological lesions, supporting integrated theranostics with multimodal imaging. In metabolic diseases, nanozymes demonstrate superior therapeutic efficacy in diabetic wound healing, diabetic retinopathy, insulin resistance, and NAFLD by orchestrating local and systemic ROS elimination, inhibiting inflammatory cytokine expression, inducing angiogenesis, and reconstructing cellular metabolic networks. For IBD, nanozymes combined with probiotic delivery systems, microenvironment-responsive release mechanisms, and immune barrier reconstruction strategies effectively promote intestinal microbiota homeostasis and epithelial barrier repair. In dermatological diseases such as psoriasis, nanozyme-mediated anti-inflammatory and apoptosis-inducing effects via ROS generation have overcome the therapeutic delays commonly associated with refractory lesions in conventional treatments. Of particular note, advances in delivery strategies and functional integration have substantially enhanced the translational potential of nanozyme-based therapies. By incorporating targeted ligands, biomimetic membrane coatings, stimuli-responsive materials, and diagnostic probes, nanozymes have enabled integrated theranostic systems, facilitating real-time pathological monitoring, precise targeted delivery, disease-responsive activation, and therapeutic efficacy feedback, thereby providing a robust platform for personalized medicine. In summary, nanozymes are reshaping the therapeutic paradigm for non-neoplastic diseases through an integrated framework that combines multi-enzyme catalysis, inflammation regulation, immune remodeling, metabolic intervention, and multimodal theranostics. As a pivotal component of next-generation precision nanomedicine, nanozymes not only offer systematic solutions to the intricate pathophysiological processes of non-neoplastic diseases but also provide a solid material foundation and theoretical support for multi-targeted, hierarchical intervention strategies. These advances collectively herald a new era of comprehensive integration and systemic regulation of functional nanomaterials in the treatment of non-neoplastic diseases. 7. Outlook 7.1 Design and Development of Next-Generation Nanozymes With the expanding potential of nanozymes in the treatment of non-neoplastic diseases, their design paradigms are evolving towards greater intelligence, precision, and functional integration. Future research will focus on biomimetic structural design, artificial intelligence (AI)-assisted high-throughput screening, microenvironment-responsive strategies, and modular multifunctional integration to achieve more efficient and controllable therapeutic interventions. (1) Biomimetic Design and AI-Assisted Screening Natural enzymes, with their remarkable substrate specificity and catalytic efficiency, have long served as ideal functional templates for artificial catalysts. Biomimetic design of nanozymes aims to emulate the structural features of natural enzyme active centers at the molecular level to enhance catalytic activity and substrate selectivity. For instance, natural PODs contain heme groups featuring iron porphyrin active centers that exhibit excellent H 2 O 2 decomposition capacity. By engineering metal-porphyrin-like moieties on the surface of nanocarriers, the catalytic performance of nanozymes can be substantially improved. Histidine-modified Fe 3 O 4 nanozymes, for example, have demonstrated over a tenfold increase in H 2 O 2 affinity and more than a twentyfold enhancement in catalytic efficiency, underscoring the immense potential of biomimetic strategies for performance optimization[191]. 11pt, fleqn, a4paper, ]LegrandOrangeBook Scheme 5 Future prospects of nanozymes in the treatment of non-neoplastic diseases. Created in https://BioRender.com. Meanwhile, the integration of AI is revolutionizing the design of nanozymes. Leveraging machine learning and molecular dynamics simulations, researchers can conduct high-throughput virtual screening across extensive nanomaterial libraries to predict key parameters such as catalytic activity, stability, and biocompatibility. Notably, the Huang group has successfully applied AI-driven models to elucidate structure–activity relationships, enabling the efficient identification of catalytically promising candidates while substantially shortening development cycles and reducing associated costs. The convergence of biomimetic strategies with AI-assisted screening offers a systematic and efficient pathway for the development of next-generation high-performance nanozymes[192]. (2) Intelligent Microenvironment-Responsive Design Non-neoplastic diseases, including IBD, RA, and AS, are typically characterized by distinct pathological microenvironments, such as localized acidosis, elevated ROS levels, or aberrant expression of inflammatory cytokines and enzymes. Rationally designing microenvironment-responsive nanozymes that activate selectively at disease sites offers a promising avenue for site-specific intervention with minimized systemic side effects. For instance, in IBD, localized pH reduction and ROS accumulation serve as critical triggers. Researchers have developed pH-sensitive precursor nanozymes that undergo structural transformation or exposure of catalytic centers under acidic conditions, enabling selective activation at diseased sites[193]. Similarly, ROS-responsive nanozymes can exploit the presence of H 2 O 2 or other reactive species to induce structural rearrangement, controlled release of active components, or enhanced catalytic activity, thereby achieving simultaneous antioxidant, anti-inflammatory, and immunomodulatory effects in highly oxidative pathological contexts[194]. These intelligent-responsive strategies not only improve treatment specificity but also mitigate systemic toxicity, providing a robust framework for precision therapy in non-neoplastic diseases. (3) Modular and Multifunctional Integration Modular assembly and multifunctional integration represent emerging trends in nanozyme design, particularly advantageous for addressing the multifactorial nature of complex diseases. By incorporating targeting moieties, therapeutic agents, and diagnostic probes within a unified nanozyme platform, synergistic enhancement of therapeutic efficacy, targeted delivery, and real-time diagnostics can be achieved. In the context of AS, for example, vascular cell adhesion molecule-1 (VCAM-1) is markedly upregulated on inflamed endothelial cells. By functionalizing nanozymes with VCAM-1-targeting peptides, site-specific delivery to atherosclerotic lesions can be realized. Moreover, therapeutic modules such as NO donors can be co-assembled with nanozymes, enabling the synchronous release of NO upon catalytic activation to exert vasodilatory, anti-inflammatory, and anti-proliferative effects on smooth muscle cells, thereby significantly enhancing cardiovascular therapeutic outcomes. The incorporation of imaging agents such as NIR fluorophores and magnetic resonance imaging probes further facilitates real-time monitoring of drug biodistribution, disease progression, and therapeutic responses, promoting personalized and image-guided treatment strategies[195]. Collectively, nanozyme development in the field of non-neoplastic diseases is undergoing a paradigm shift from single-function catalytic materials to intelligent, multifunctional, and integrated therapeutic platforms. Looking ahead, biomimetic structural design, AI-assisted discovery, microenvironment responsiveness, and modular integration are poised to become the cornerstones of next-generation nanozyme engineering, offering powerful technological support for precision medicine and individualized therapies. 7.2 Development of Nanozymes Based on Emerging Materials and Structural Innovations The next generation of nanozymes will prioritize innovations in materials and structural design to enhance catalytic performance, multifunctional integration, and biological adaptability. Future research efforts are expected to focus on several key directions: (1) Construction of Advanced Material Systems Emerging material platforms such as metal–organic frameworks (MOFs), covalent organic frameworks (COFs), and two-dimensional materials (e.g., MXene, black phosphorus) have garnered considerable attention in nanozyme design owing to their high surface areas, tunable electronic structures, and abundant surface functional groups[196]. For example,Huang’s team developed ultra-small cerium-based metal–organic frameworks (Ce-MOF) nanozymes[197]. These nanozymes mimic SOD and CAT activities to efficiently scavenge ROS, inhibit oxidative stress and inflammation, promote corneal epithelial repair, and restore tear secretion, achieving effective antioxidant treatment for DED. (2) Heterostructure Engineering and Interface Modulation The construction of heterostructures, such as core–shell architectures, heterojunctions, and SACs, enables precise modulation of the surface electronic states and catalytically active sites of nanozymes, thereby markedly improving catalytic efficiency and substrate specificity[185]. A representative example is the Fe 3 O 4 @Pt core–shell nanozyme developed by Gao and colleagues[198], which exhibits dual POD and OXD activities. This multifunctional platform facilitates cascade ROS scavenging and hypoxia alleviation in the inflammatory microenvironment of OA, ultimately promoting cartilage regeneration. By leveraging heterointerface engineering, this strategy optimizes catalytic pathways and provides an innovative material solution for the treatment of chronic inflammatory diseases such as OA. (3) Biomimetic Structural and Functional Design The construction of nanozyme scaffolds that mimic the hierarchical architecture of biological tissues, in combination with advanced fabrication techniques such as 3D printing and self-assembly, has emerged as a promising approach to improve therapeutic efficacy by enhancing tissue penetration and retention. Xu et al.[199] developed a biomimetic nanozyme loaded with three drugs and targeting IIMe. Camouflaged with a hybrid exosome-cell membrane derived from M2 macrophages, this nanozyme provides an efficient and immunologically inert strategy for multimodal GA therapy. It holds significant potential to mitigate challenges in clinical translation and could be adapted for the treatment of various inflammatory diseases. math_shortcuts 7.3 Design of Nanozymes with High Catalytic Activity and Specificity Future advancements in nanozyme catalysis will focus on achieving two core objectives: ”precision catalysis” and ”dynamic environmental adaptability.” By leveraging atomic-level structural modulation, targeted functionalization, and multi-responsive mechanisms, nanozymes are expected to exhibit markedly enhanced catalytic activity and targeting specificity in the treatment of non-neoplastic diseases. Atomic-level activity regulation Strategies such as single-atom doping, alloying, and surface defect engineering enable precise tuning of the nanozyme’s electronic states and substrate binding sites, thereby elevating catalytic efficiency to levels comparable to, or even exceeding, those of natural enzymes. For instance,Liu et al. engineered an Ir-N5 single-atom nanozyme (Ir-N5 SA) for solid tumor therapy[200]. Asymmetric electron distribution induced by Ir-N5 coordination enhanced adsorption of endogenous substrates (e.g., H₂O₂), boosting triple-enzyme mimetic activities (POD/CAT/GPx). This nanozyme disrupts metabolic homeostasis in the tumor microenvironment via simultaneous ·OH generation and GSH depletion, while suppressing mitochondrial complex I to reduce ATP synthesis by ≥70%. The resultant dual metabolic disruption synergistically induced tumor cell apoptosis, achieving >90% tumor suppression in vivo. (2) Enhancement of targeting specificity Nanozyme targeting has been advanced through molecular imprinting, antibody conjugation, and inflammation-responsive surface coatings to improve selective recognition and localization at pathological sites. Fan et al. employed a ferritin (HFn)-based carrier to deliver Pt NPs targeting transferrin receptor 1 (TfR1), which is overexpressed in hypoxic regions of nasopharyngeal carcinoma[201]. By catalyzing H 2 O 2 decomposition to alleviate hypoxia, the Pt–HFn nanozyme significantly enhanced radiosensitivity. Tumor accumulation in patient-derived xenograft models increased fourfold, extending animal survival. Liu et al. developed MnO 2 nanozymes functionalized with MMP-9-sensitive peptides for targeted activation in arthritic synovium, characterized by MMP-9 overexpression. This enabled selective ROS scavenging and hypoxia relief at the disease site while minimizing off-target catalytic side effects in healthy tissues[202]. (3) Environmentally adaptive catalytic design By integrating multi-stimuli responsive elements such as pH, ROS, and enzyme triggers, nanozymes can dynamically modulate catalytic activity to better function within complex pathological microenvironments. Li et al. designed ultrasmall edible phycocyanin–iron nanozymes (<10 nm) exhibiting high stability in the acidic milieu of alcoholic acute gastritis. These nanozymes penetrated the gastric mucosa to efficiently scavenge ROS and promote tissue repair[203]. A single-dose treatment outperformed the clinical drug omeprazole, simultaneously activating SOD- and CAT-like activities under acidic conditions to neutralize oxidative stress and suppress pro-inflammatory cytokines TNF-α and IL-6.Additionally,Li et al. developed a pH-responsive sulfur quantum dot (SQD) nanozyme for full-stage infected bone defects (IBDs) therapy. It mimics SOD, CAT, and POD activities, generating ROS to eliminate bacteria in the acidic microenvironment of early infection, then switching to SOD-CAT-like behavior to scavenge excess ROS and promote M2 macrophage polarization in the mid-inflammatory stage, and finally facilitating bone repair in the late stage. Encapsulated in GelMA hydrogel for in vivo IBDs treatment, it achieved programmed antibacterial effects and immunomodulation, promoting bone microenvironment remodeling and enhancing IBDs healing. math_shortcuts 7.4 Design and Optimization of Multimodal Therapeutic Strategies Nanozymes, owing to their unique catalytic activity and exceptional stability, have demonstrated remarkable advantages in the treatment of non-neoplastic diseases. By efficiently scavenging ROS and precisely modulating oxidative stress levels, nanozymes effectively suppress inflammatory cascades. When combined with other therapeutic modalities, multimodal synergistic strategies based on nanozymes hold great promise to overcome the limitations of conventional monotherapies, enhancing lesion targeting and overall therapeutic efficacy. (1) Synergistic enhancement of nanozymes and photothermal therapy Photothermal nanozymes responsive to NIR light, such as PB and CuS, can generate localized hyperthermia upon irradiation while simultaneously exhibiting enzymatic catalytic functions, thereby achieving dual-mode therapy. For example,the multifunctional composite iron-copper bimetallic single-atom nanozyme efficiently eradicated pathogens via photothermal effects in a skin infection model, while its POD-like activity scavenged inflammation-associated ROS to suppress inflammatory responses[204]. Furthermore, this composite modulated macrophage polarization and promoted angiogenesis and epithelial regeneration, significantly accelerating wound healing. (2) Synergistic therapy combining nanozymes with chemotherapy/anti-inflammatory drugs Nanozymes regulate redox homeostasis to potentiate the efficacy of conventional drugs while mitigating side effects. For instance, CeO 2 nanozymes loaded with methotrexate effectively alleviated oxidative damage by ROS clearance, while methotrexate inhibited inflammatory cell proliferation in RA, resulting in a synergistic therapeutic effect[205]. Similarly, MnO 2 nanozymes carrying dexamethasone (Dex) catalyzed the decomposition of excess H 2 O 2 to release oxygen, alleviating hypoxia in inflammatory tissues and promoting macrophage polarization toward the anti-inflammatory M2 phenotype. Dex further augmented the anti-inflammatory response, demonstrating significant therapeutic potential[206]. (3) Integration of nanozymes with sonodynamic therapy The combination of sonodynamic therapy and nanozyme catalysis enables efficient regulation of deep tissue inflammation. For example, Cheng et al.[207] developed Au/TNT@PG, an activatable nanozyme for MRSA biofilm-induced osteomyelitis. Integrating ultrasound-absorbing Au/TNTs with cationic polyguanidine (PG), it generates 1 O 2 (sonodynamic therapy) and catalyzes H 2 O 2 to ·OH conversion in acidic biofilms. PG enhances biofilm penetration/bacterial capture, enabling synergistic sonocatalytic eradication. Remotely, it promotes M2 macrophage polarization (reducing inflammation) and osteogenesis, providing a targeted nanotherapeutic strategy. (4) Synergistic effects of nanozymes and magnetic hyperthermia therapy Magnetic nanozymes accumulate selectively at lesion sites under alternating magnetic fields, inducing localized hyperthermia alongside catalytic therapy. Zhao et al.[208] engineered magnetic iron oxide nanoparticles as nanozymes for head and neck cancer therapy in murine models. Utilizing an alternating magnetic field-based system, they enabled magnetothermal therapy by inducing localized heating (~40°C) at the tumor site. This temperature elevation rapidly disrupted epithelial tumor structures within 5-10 minutes, causing significant cancer cell damage/death. Pathological analysis confirmed tumor cell ablation, demonstrating effective tumor growth suppression and a potential minimally invasive therapeutic strategy. (5) Nanozyme-driven gas therapy strategies Nanozymes catalyze endogenous substrates to generate therapeutic gases, modulating vascular tone, inhibiting platelet aggregation, or degrading fibrotic barriers. For example,Cu-Fe bimetallic nanozyme catalyzes the reduction of endogenous NO precursors (e.g., nitrite) to generate NO, thereby promoting vasodilation of vascular smooth muscle via activation of the cGMP signaling pathway[209]. (6) Nanozyme-mediated microbial ecological regulation Targeting the microbiota–immune interaction network, nanozymes exhibit combined antibacterial, antioxidative, and probiotic-modulating effects to facilitate the treatment of inflammation-related diseases. For instance,IP NPs-RSNO nanozyme markedly enhances antibacterial efficacy against multidrug-resistant pathogens through a synergistic combination of photothermal therapy, potentiated enzymatic activity, and NO liberation[210].Ultrafine Au/Cu-LNF nanozyme potentiates antibacterial and wound-healing efficacy via synergistic catalytic ·OH generation, NIR-enhanced POD-like activity, and bacterial confinement mechanisms against drug-resistant pathogens[211] ( Scheme 5 ). Acknowledgements L. Mei, X. Wang, and Z. Hu contributed equally to this work. This work was supported by the China Scholarship Council (CSC, 202106270027 to Q.D.) and the Chengdu Municipal Health Commission & Chengdu University of Traditional Chinese Medicine 2024 Annual Joint Commission-University Innovation Fund (WXLH202402008) Author contributions Ling Mei : Writing – review & editing. Xikai Wang : Writing – review & editing. Zhuang Hu: Writing – review & editing. Jierui Yan : Writing – review & editing. Xiaobo Wang : Writing – review & editing. Ya Hou : Writing – review & editing. Pengfei Zhang : Writing – review & editing. Qihang Ding : Writing – review & editing. Declaration of interests The authors declare no competing interests. 11pt, fleqn, a4paper, ]LegrandOrangeBook References [1] Doroszkiewicz J, Mroczko J, Winkel I, et al.Metabolic and Immune System Dysregulation: Unraveling the Connections between Alzheimer’s Disease, Diabetes, Inflammatory Bowel Diseases, and Rheumatoid Arthritis.Journal of Clinical Medicine,2024,13:5057[2] Wang A, Guan B, Zhang H, et al.Danger-associated metabolites trigger metaflammation: A crowbar in cardiometabolic diseases.Pharmacological Research,2023,198:106983[3] Domingo E, Marques P, Francisco V, et al.Targeting systemic inflammation in metabolic disorders. A therapeutic candidate for the prevention of cardiovascular diseases?Pharmacol Res,2024,200:107058[4] Xiao G, Li H, Zhao Y, et al.Nanoceria-Based Artificial Nanozymes: Review of Materials and Applications.ACS Applied Nano Materials,2022,5:14147-14170[5] Cheng F, Kotha S, Fu M, et al.Nanozyme enabled protective therapy for neurological diseases.Nano Today,2024,54:102142[6] Zhang Y, Liu W, Wang X, et al.Nanozyme-Enabled Treatment of Cardio- and Cerebrovascular Diseases.Small,2023,19:e2204809[7] Wang H, Cui Z, Wang X, et al.Therapeutic Applications of Nanozymes in Chronic Inflammatory Diseases.Biomed Res Int,2021,2021:9980127[8] Yang L, Dong S, Gai S, et al.Deep Insight of Design, Mechanism, and Cancer Theranostic Strategy of Nanozymes.Nanomicro Lett,2023,16:28[9] Cao S, Dong S, Feng L, et al.Engineering Strain-Defects to Enhance Enzymatic Therapy and Induce Ferroptosis.Adv Mater,2024,36:e2408502[10] Chen Z, Li B, Zhang Y, et al.Bioinspired rational design of nanozymes.Materials Horizons,2025,[11] Ding Q, Ding L, Xiang C, et al.pH-Responsive AIE Photosensitizers for Enhanced Antibacterial Therapy.Angewandte Chemie International Edition,2025,n/a:e202506505[12] Gu L, Sun Y, Bai T, et al.Functional nanozyme system for synergistic tumor immunotherapy via cuproptosis and ferroptosis activation.Journal of Nanobiotechnology,2025,23:212[13] Wang H, Yang Y, Yu H, et al.Self-Cascade API Nanozyme for Synergistic Anti-Inflammatory, Antioxidant, and Ferroptosis Modulation in the Treatment of Corneal Neovascularization.Small,2025,21:e2407751[14] Ding Q, Liu J, Wang Y, et al.Dual-laser “808 and 1,064 nm” strategy that circumvents the Achilles’ heel of photothermal therapy.Proceedings of the National Academy of Sciences,2025,122:e2503574122[15] Rao L, Yuan Y, Shen X, et al.Designing nanotheranostics with machine learning.Nat Nanotechnol,2024,19:1769-1781[16] Mohapatra A, Park I K.Recent Advances in ROS-Scavenging Metallic Nanozymes for Anti-Inflammatory Diseases: A Review.Chonnam Med J,2023,59:13-23[17] Ding Q, Wang C, Wang H, et al.Rabies Virus Targeting NIR-II Phototheranostics.J Am Chem Soc,2025,147:16661-16673[18] Ju Y, Liu X, Ye X, et al.Nanozyme-Based Remodeling of Disease Microenvironments for Disease Prevention and Treatment: A Review.ACS Applied Nano Materials,2023,6:13792-13823[19] Gao L, Zhuang J, Nie L, et al.Intrinsic peroxidase-like activity of ferromagnetic nanoparticles.Nature Nanotechnology,2007,2:577-583[20] Fu R, Ma Z, Zhao H, et al.Research Progress in Iron-Based Nanozymes: Catalytic Mechanisms, Classification, and Biomedical Applications.Analytical Chemistry,2023,95:10844-10858[21] Xie C, Liao J, Li Y, et al.Synergistic anti-inflammatory effect of cascade nanozymes for neural recovery in ischemic stroke.Chinese Chemical Letters,2025,110956[22] Han J, Kim Y S, Lim M-Y, et al.Dual Roles of Graphene Oxide To Attenuate Inflammation and Elicit Timely Polarization of Macrophage Phenotypes for Cardiac Repair.ACS Nano,2018,12:1959-1977[23] Ding Q, Huang S, Zhang Z, et al.Integration of Photodiagnosis and Therapy Guided by Micro/Nanorobots.Adv Mater,2025,37:e2420359[24] Fan L, Sun P, Huang Y, et al.One-Pot Synthesis of Fe/N-Doped Hollow Carbon Nanospheres with Multienzyme Mimic Activities against Inflammation.ACS Applied Bio Materials,2020,3:1147-1157[25] Ding Q, Rha H, Yoon C, et al.Regulated cell death mechanisms in mitochondria-targeted phototherapy.J Control Release,2025,382:113720[26] Xue B, Lu Y, Wang S, et al.The emerging role of nanozymes in ocular antioxidant therapy.Nano Today,2024,58:102448[27] Mei L, Ding Q, Xie Y, et al.Self-propelling intelligent nanomotor: A dual-action photothermal and starvation strategy for targeted deep tumor destruction.Biomaterials,2025,315:122968[28] Bardi G, Boselli L, Pompa P P.Anti-inflammatory potential of platinum nanozymes: mechanisms and perspectives.Nanoscale,2023,15:14284-14300[29] Xia H, Li N, Zhong X, et al.Metal-Organic Frameworks: A Potential Platform for Enzyme Immobilization and Related Applications.Front Bioeng Biotechnol,2020,8:695[30] Liu X, Zhang H, Hao C, et al.Chiral Se@CeO(2) superparticles for ameliorating Parkinson’s disease.Nanoscale,2023,15:4367-4377[31] Ling D, Hyeon T.Chemical Design of Biocompatible Iron Oxide Nanoparticles for Medical Applications.Small,2013,9:1450-1466[32] Wang L, Yuan X, Cai Q, et al.Mitochondria-targeting Cu2-xSe-TPP with dual enzyme activity alleviates Alzheimer’s disease by modulating oxidative stress.Colloids and Surfaces B: Biointerfaces,2025,245:[33] Xiang K, Wu H, Liu Y, et al.MOF-derived bimetallic nanozyme to catalyze ROS scavenging for protection of myocardial injury.Theranostics,2023,13:2721-2733[34] Feng S, Peng X, Deng Y, et al.Biomimetic Nanozyme-Decorated Smart Hydrogel for Promoting Chronic Refractory Wound Healing.ACS Applied Materials & Interfaces,2024,16:59862-59879[35] Wang F, Yuan H, Shen J, et al.Nanozymes with Broad-Spectrum Scavenging of Reactive Oxygen Species (ROS) Alleviate Inflammation in Acute Liver Injury.ACS Materials Letters,2024,6:1304-1316[36] Mao M, Guan X, Wu F, et al.CoO Nanozymes with Multiple Catalytic Activities Regulate Atopic Dermatitis.Nanomaterials,2022,12:[37] Dai S, Yao L, Liu L, et al.Carbon dots-supported Zn single atom nanozymes for the catalytic therapy of diabetic wounds.Acta Biomaterialia,2024,186:454-469[38] Hu R, Dai C, Dong C, et al.Living Macrophage-Delivered Tetrapod PdH Nanoenzyme for Targeted Atherosclerosis Management by ROS Scavenging, Hydrogen Anti-inflammation, and Autophagy Activation.ACS Nano,2022,16:15959-15976[39] Luo W-C, Bao L-N, Zhang Y, et al.A Ru3+-functionalized-NMOF nanozyme as an inhibitor and disaggregator of β-amyloid aggregates.Journal of Materials Chemistry B,2024,12:12239-12250[40] Xu H, Ding X, Li L, et al.Tri-element nanozyme PtCuSe as an ingenious cascade catalytic machine for the amelioration of Parkinson’s disease-like symptoms.Frontiers in Bioengineering and Biotechnology,2023,11:[41] Zhang L, Li A, Shen M, et al.Palladium–platinum bimetallic modified MXene nanozyme for highly sensitive detection of active substances with acetylcholinesterase inhibitory effect.Talanta,2025,282:[42] Chen S, Luo X, Sun Y, et al.A novel metabolic reprogramming strategy for the treatment of targeting to heart injury-mediated macrophages.International Immunopharmacology,2023,122:110377[43] Wang L, Gao Z, Tian M, et al.A Nanosystem Alleviates Severe Acute Pancreatitis via Reactive Oxygen Species Scavenging and Enhancing Mitochondrial Autophagy.Nano Lett,2025,25:8644-8654[44] Li Q, Ding X, Chang Z, et al.Metal–Organic Framework Based Nanozyme System for NLRP3 Inflammasome‐Mediated Neuroinflammatory Regulation in Parkinson’s Disease.Advanced Healthcare Materials,2023,13:[45] Liu Y, Cheng Y, Zhang H, et al.Integrated cascade nanozyme catalyzes in vivo ROS scavenging for anti-inflammatory therapy.Sci Adv,2020,6:eabb2695[46] Liu C, Zhang W, Zhang H, et al.Biomimetic engineering of a neuroinflammation-targeted MOF nanozyme scaffolded with photo-trigger released CO for the treatment of Alzheimer’s disease.Chemical Science,2024,15:13201-13208[47] Liu X, Chen B, Chen J, et al.A Cardiac‐Targeted Nanozyme Interrupts the Inflammation‐Free Radical Cycle in Myocardial Infarction.Advanced Materials,2023,36:[48] Xu D, Wu L, Yao H, et al.Catalase-Like Nanozymes: Classification, Catalytic Mechanisms, and Their Applications.Small,2022,18:e2203400[49] Li S, Ding H, Chang J, et al.Bimetallic oxide nanozyme-mediated depletion of glutathione to boost oxidative stress for combined nanocatalytic therapy.J Colloid Interface Sci,2022,623:787-798[50] Ding Q, Chen H, Zhang Y, et al.Innovative integration of nanomedicines and phototherapy to modulate autophagy for enhanced tumor eradication.Journal of Controlled Release,2025,377:855-879[51] Xiang J, Yang X, Tan M, et al.NIR-enhanced Pt single atom/g-C(3)N(4) nanozymes as SOD/CAT mimics to rescue ATP energy crisis by regulating oxidative phosphorylation pathway for delaying osteoarthritis progression.Bioact Mater,2024,36:1-13[52] Zhang J, Wang Z, Lin X, et al.Mn−Ce Symbiosis: Nanozymes with Multiple Active Sites Facilitate Scavenging of Reactive Oxygen Species (ROS) Based on Electron Transfer and Confinement Anchoring.Angewandte Chemie,2024,137:[53] Wang Y, Ding Q, Ma G, et al.Mucus-Penetrable Biomimetic Nanoantibiotics for Pathogen-Induced Pneumonia Treatment.ACS Nano,2024,18:31349-31359[54] Yan B C, Cao J, Liu J, et al.Dietary Fe(3)O(4) Nanozymes Prevent the Injury of Neurons and Blood-Brain Barrier Integrity from Cerebral Ischemic Stroke.ACS Biomater Sci Eng,2021,7:299-310[55] Lei X, Qiu l, Du F.ZIF-8@Pt Nanozyme Used for Scavenging Reactive Oxygen Species in the Treatment of Rheumatoid Arthritis.JOURNAL OF SICHUAN UNIVERSITY (MEDICAL SCIENCES),2024,55:826-837[56] Gu Z, Zhong D, Hou X, et al.Unraveling Ros Conversion Through Enhanced Enzyme‐Like Activity with Copper‐Doped Cerium Oxide for Tumor Nanocatalytic Therapy.Advanced Science,2023,11:[57] Ruan H, Zhang S, Wang H, et al.Single-Atom Pd/CeO2 Nanostructures for Mimicking Multienzyme Activities.ACS Applied Nano Materials,2022,5:6564-6574[58] Jiao L, Xu W, Zhang Y, et al.Boron-doped Fe-N-C single-atom nanozymes specifically boost peroxidase-like activity.Nano Today,2020,35:100971[59] Dong J, Huang Z, Fu Y, et al.FeCu–P/carbon dots with multi-enzyme activity catalyze reactive oxygen species production for enhanced antibacterial activity.Carbon,2025,243:120478[60] Cao H, Yuan Y, Zhao R, et al.Deciphering the Catalytic Mechanism of Peroxidase-like Activity of Iron Sulfide Nanozymes.ACS Appl Mater Interfaces,2024,16:30958-30966[61] Feng W, Han X, Hu H, et al.2D vanadium carbide MXenzyme to alleviate ROS-mediated inflammatory and neurodegenerative diseases.Nature Communications,2021,12:2203[62] Mohsin M, Shams F, Li H, et al.Nanozymes in neuropathic pain: strategies bridging oxidative stress, mitochondrial repair, and neuroimmune modulation for targeted therapy.Journal of Neuroinflammation,2025,22:156[63] Ding Q, Xu X, Li Y, et al.Diverse interactions between AIEgens and biomolecules/organisms: Advancing from strategic design to precision theranostics.Chem,2024,10:2031-2073[64] M. R K, Mehta D, Singh S.CeO2- and Mn3O4-based nanozymes exhibit scavenging of singlet oxygen species and hydroxyl radicals.Nanoscale,2025,[65] Shi J, Zhang Y, Fang X, et al.Photoswitchable Antioxidant and Prooxidant Activities of Mg-Doped Carbon Dot Nanozymes as Antibacterial and Anti-Inflammatory Agents.ACS Applied Materials & Interfaces,2025,17:26467-26479[66] Zhang S, Gao X J, Ma Y, et al.A bioinspired sulfur–Fe–heme nanozyme with selective peroxidase-like activity for enhanced tumor chemotherapy.Nature Communications,2024,15:10605[67] Shahraki S, Vaziri E, Saboury A A, et al.Biomedical potential of nanozymes: Harnessing redox enzyme mimicry for theranostic applications.Coordination Chemistry Reviews,2024,517:[68] Liu T, Xiao B, Xiang F, et al.Ultrasmall copper-based nanoparticles for reactive oxygen species scavenging and alleviation of inflammation related diseases.Nature Communications,2020,11:[69] Jiang W, Li Q, Zhang R, et al.Chiral metal-organic frameworks incorporating nanozymes as neuroinflammation inhibitors for managing Parkinson’s disease.Nature Communications,2023,14:[70] Liu Y, Liu Y, Shi P, et al.Single-atom nanozyme liposome-integrated microneedles for in situ drug delivery and anti-inflammatory therapy in Parkinson’s disease.J Nanobiotechnology,2024,22:643[71] Zhang X, Liu B, Lu Y, et al.Self-Propelled Peg-Fe3o4@ Mno2 Janus Magnetic Nanorobots as Enzyme-Like for Dynamic Detection of Gsh and Efficient Degradation of Tch.Available at SSRN 4140964,[72] Corsi F, Deidda Tarquini G, Urbani M, et al.The Impressive Anti-Inflammatory Activity of Cerium Oxide Nanoparticles: More than Redox?Nanomaterials,2023,13:2803[73] Wang H, Cui Z, Wang X, et al.Therapeutic Applications of Nanozymes in Chronic Inflammatory Diseases.BioMed Research International,2021,2021:9980127[74] Zeng J, Huang S, Du F, et al.[Advances in the Application of Nanozymes in Joint Disease Therapy].Sichuan Da Xue Xue Bao Yi Xue Ban,2024,55:800-806[75] Meng T, He D, Han Z, et al.Nanomaterial-Based Repurposing of Macrophage Metabolism and Its Applications.Nanomicro Lett,2024,16:246[76] Lasola J J M, Cottingham A L, Scotland B L, et al.Immunomodulatory Nanoparticles Mitigate Macrophage Inflammation via Inhibition of PAMP Interactions and Lactate-Mediated Functional Reprogramming of NF-κB and p38 MAPK.Pharmaceutics,2021,13:1841[77] Repellin M, Guerin H, Catania G, et al.ROS-based nanomedicines for anti-inflammatory therapies.Redox Experimental Medicine,2023,2023:[78] Wu Y, Ta H T.Different approaches to synthesising cerium oxide nanoparticles and their corresponding physical characteristics, and ROS scavenging and anti-inflammatory capabilities.J Mater Chem B,2021,9:7291-7301[79] Liang S, Tian X, Wang C.Nanozymes in the Treatment of Diseases Caused by Excessive Reactive Oxygen Specie.J Inflamm Res,2022,15:6307-6328[80] Wei H, Huang H, He H, et al.Pt-Se Hybrid Nanozymes with Potent Catalytic Activities to Scavenge ROS/RONS and Regulate Macrophage Polarization for Osteoarthritis Therapy.Research (Wash D C),2024,7:0310[81] Xu X, Zhang Y, Meng C, et al.Nanozymes in cancer immunotherapy: metabolic disruption and therapeutic synergy.J Mater Chem B,2024,12:9111-9143[82] Ding Q, Liu H, Yan L, et al.Engineering a Multifunctional Nanozyme Platform for Synergistic Melanoma Therapy: Integrating Enzyme Activity, Immune Activation, and Low-Temperature Photothermal Effects.Angewandte Chemie International Edition,2025,n/a:e202505911[83] Da J, Li Y, Zhang K, et al.Functionalized Prussian Blue Nanozyme as Dual-Responsive Drug Therapeutic Nanoplatform Against Maxillofacial Infection via Macrophage Polarization.Int J Nanomedicine,2022,17:5851-5868[84] Xu S, Zhang Y, Ding X, et al.Intestinal microbiota affects the progression of colorectal cancer by participating in the host intestinal arginine catabolism.Cell Reports,2025,44:[85] Xiang Y, Zhang M, Jiang D, et al.The role of inflammation in autoimmune disease: a therapeutic target.Front Immunol,2023,14:1267091[86] Shao F, Liu Q, Zhu Y, et al.Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis.Nature Communications,2021,12:6540[87] Zhang S-J, Xu R, He S-B, et al.Nanozyme-driven multifunctional dressings: moving beyond enzyme-like catalysis in chronic wound treatment.Military Medical Research,2025,12:27[88] Fu Z, Zhang M, Huang Y, et al.DNA binding effects of LDH nanozyme for aseptic osteolysis mitigation through STING pathway modulation.J Nanobiotechnology,2025,23:384[89] Chen Q, Duan X, Yu Y, et al.Target Functionalized Carbon Dot Nanozymes with Dual‐Model Photoacoustic and Fluorescence Imaging for Visual Therapy in Atherosclerosis.Advanced Science,2023,11:[90] Lv F, Fang H, Huang L, et al.Curcumin Equipped Nanozyme‐Like Metal−Organic Framework Platform for the Targeted Atherosclerosis Treatment with Lipid Regulation and Enhanced Magnetic Resonance Imaging Capability.Advanced Science,2024,11:[91] Wang L, Zhang X, Zhang H, et al.Novel Metal-Free Nanozyme for Targeted Imaging and Inhibition of Atherosclerosis via Macrophage Autophagy Activation to Prevent Vulnerable Plaque Formation and Rupture.ACS Applied Materials & Interfaces,2024,16:51944-51956[92] Wang C, He Y, Tang J, et al.Chondroitin sulfate functionalized nanozymes inhibit the inflammation feedback loop for enhanced atherosclerosis therapy by regulating intercellular crosstalk.International Journal of Biological Macromolecules,2024,282:[93] Wang S, Zhang J, Li W, et al.Hyaluronic acid-guided assembly of ceria nanozymes as plaque-targeting ROS scavengers for anti-atherosclerotic therapy.Carbohydrate Polymers,2022,296:[94] He H, Han Q, Wang S, et al.Design of a Multifunctional Nanozyme for Resolving the Proinflammatory Plaque Microenvironment and Attenuating Atherosclerosis.ACS Nano,2023,17:14555-14571[95] Zhong Y, Yang Y, Xu Y, et al.Design of a Zn-based nanozyme injectable multifunctional hydrogel with ROS scavenging activity for myocardial infarction therapy.Acta Biomaterialia,2024,177:62-76[96] Chen S, Luo X, Sun Y, et al.A novel metabolic reprogramming strategy for the treatment of targeting to heart injury-mediated macrophages.International Immunopharmacology,2023,122:[97] Ma M, Gao N, Li X, et al.A Biocompatible Second Near-Infrared Nanozyme for Spatiotemporal and Non-Invasive Attenuation of Amyloid Deposition through Scalp and Skull.ACS Nano,2020,14:9894-9903[98] Jia Z, Yuan X, Wei J-a, et al.A Functionalized Octahedral Palladium Nanozyme as a Radical Scavenger for Ameliorating Alzheimer’s Disease.ACS Applied Materials & Interfaces,2021,13:49602-49613[99] Ma M, Liu Z, Gao N, et al.Self-Protecting Biomimetic Nanozyme for Selective and Synergistic Clearance of Peripheral Amyloid-β in an Alzheimer’s Disease Model.Journal of the American Chemical Society,2020,142:21702-21711[100] Liu Y, Liu Y, Shi P, et al.Single-atom nanozyme liposome-integrated microneedles for in situ drug delivery and anti-inflammatory therapy in Parkinson’s disease.Journal of Nanobiotechnology,2024,22:[101] Ma X, Hao J, Wu J, et al.Prussian Blue Nanozyme as a Pyroptosis Inhibitor Alleviates Neurodegeneration.Advanced Materials,2022,34:[102] Ji W, Li Y, Peng H, et al.Self‐Catalytic Small Interfering RNA Nanocarriers for Synergistic Treatment of Neurodegenerative Diseases.Advanced Materials,2021,34:[103] Gong Y, Huang A, Guo X, et al.Selenium-core nanozymes dynamically regulates Aβ & neuroinflammation circulation: Augmenting repair of nervous damage.Chemical Engineering Journal,2021,418:[104] Huang W, Tian Y, Ma J, et al.Neutrophil membrane-based biomimetic metal-polyphenol self-assembled nanozyme for the targeting treatment of early brain injury following subarachnoid hemorrhage.Chemical Engineering Journal,2024,498:[105] Gao F, Liang W, Chen Q, et al.A Curcumin-Decorated Nanozyme with ROS Scavenging and Anti-Inflammatory Properties for Neuroprotection.Nanomaterials,2024,14:[106] Ding Q, Zhang S, Kim J S.A lysosomal-targeted Pt(II) metallacycle for NIR-II fluorescence imaging guided highly efficient tumor immunogenic cell death.Science China Chemistry,2024,67:3508-3509[107] Wang X, Qin X, Liu Y, et al.Plasmonic Supramolecular Nanozyme‐Based Bio‐Cockleburs for Synergistic Therapy of Infected Diabetic Wounds.Advanced Materials,2024,36:[108] Mandakhbayar N, Ji Y, El-Fiqi A, et al.Double hits with bioactive nanozyme based on cobalt-doped nanoglass for acute and diabetic wound therapies through anti-inflammatory and pro-angiogenic functions.Bioactive Materials,2024,31:298-311[109] Chen S, Luo X, Ma R, et al.Promotes M1-polarization and diabetic wound healing using Prussian blue nanozymes.International Immunopharmacology,2024,141:113009[110] Pu C, Wang Y, Xiang H, et al.Zinc-based Polyoxometalate Nanozyme Functionalized Hydrogels for optimizing the Hyperglycemic-Immune Microenvironment to Promote Diabetic Wound Regeneration.Journal of Nanobiotechnology,2024,22:[111] Jiang S, Xie D, Hu Z, et al.Enhanced diabetic wound healing with injectable hydrogel containing self-assembling nanozymes.Journal of Controlled Release,2024,372:265-280[112] Shen B, Yan Z, Wang Y, et al.Nanozyme-chitosan-aerogel immobilized enzyme-driven biocatalytic cascade for therapeutic engineering of diabetic wounds.Carbohydrate Polymers,2025,347:122690[113] Chen L, Xing S, Lei Y, et al.A Glucose‐Powered Activatable Nanozyme Breaking pH and H2O2 Limitations for Treating Diabetic Infections.Angewandte Chemie International Edition,2021,60:23534-23539[114] Gui S, Tang W, Huang Z, et al.Ultrasmall Coordination Polymer Nanodots Fe‐Quer Nanozymes for Preventing and Delaying the Development and Progression of Diabetic Retinopathy.Advanced Functional Materials,2023,33:[115] Tian M, Li Z, Liu S, et al.Ultrasmall copper nanodots eye drops for microenvironment regulation of diabetes retinopathy by relieving hypoxia and inhibiting HIF-1α/VEGF signaling pathway.Chemical Engineering Journal,2024,491:152130[116] Zhou L, Lan K, Huang X, et al.A Novel Photosynthetic Biohybrid System for Microenvironment Regulation of Diabetes Retinopathy through Continuous Oxygen Supply and Nanozyme Cascade Reaction.Advanced Functional Materials,2023,33:[117] Wang Z, Zhang Y, Chen S, et al.Multifunctional CeO2 nanozymes for mitigating high-glucose induced senescence and enhancing bone regeneration in type 2 diabetes mellitus.Chemical Engineering Journal,2024,485:149842[118] Li X, Zhu W, Liu R, et al.Cerium Oxide Nanozymes Improve Skeletal Muscle Function in Gestational Diabetic Offspring by Attenuating Mitochondrial Oxidative Stress.ACS Omega,2024,9:21851-21863[119] Shen H, Fu Y, Liu F, et al.AuCePt porous hollow cascade nanozymes targeted delivery of disulfiram for alleviating hepatic insulin resistance.Journal of Nanobiotechnology,2024,22:[120] Lin Y, Wang Y, Zhang Q, et al.Single-Atom Ce-N-C Nanozyme Ameliorates Type 2 Diabetes Mellitus by Improving Glucose Metabolism Disorders and Reducing Oxidative Stress.Biomolecules,2024,14:[121] Yang H, Xia L, Ye X, et al.Ultrathin Niobium Carbide MXenzyme for Remedying Hypertension by Antioxidative and Neuroprotective Actions.Angewandte Chemie International Edition,2023,62:[122] Yang D, Liu K, Cai C, et al.Target-Engineered Liposomes Decorated with Nanozymes Alleviate Liver Fibrosis by Remodeling the Liver Microenvironment.ACS Applied Materials & Interfaces,2024,16:64536-64553[123] Sun Y, Xu T, Qian Y, et al.NOS-like activity of CeO2 nanozymes contributes to diminishing the vascular plaques.Journal of Nanobiotechnology,2024,22:[124] Dong F, Hao L, Wang L, et al.Clickable nanozyme enhances precise colonization of probiotics for ameliorating inflammatory bowel disease.Journal of Controlled Release,2024,373:749-765[125] Jiang K, Cao X, Wu H, et al.2D Nanozymes Modulate Gut Microbiota and T‐Cell Differentiation for Inflammatory Bowel Disease Management.Advanced Healthcare Materials,2023,13:[126] Zeng F, Shi Y, Wu C, et al.A drug-free nanozyme for mitigating oxidative stress and inflammatory bowel disease.Journal of Nanobiotechnology,2022,20:[127] Wang C-P J, Ko G R, Lee Y Y, et al.Polymeric DNase-I nanozymes targeting neutrophil extracellular traps for the treatment of bowel inflammation.Nano Convergence,2024,11:[128] Zhu D, Wu H, Jiang K, et al.Zero‐Valence Selenium‐Enriched Prussian Blue Nanozymes Reconstruct Intestinal Barrier against Inflammatory Bowel Disease via Inhibiting Ferroptosis and T Cells Differentiation.Advanced Healthcare Materials,2023,12:[129] Zhang D, Wan H, Zhao R, et al.Eudragit S100 coated iron oxide-chitosan nanocomposites for colon targeting of 5-aminosalicylic acid ameliorate ulcerative colitis by improving intestinal barrier function and inhibiting NLRP3 inflammasome.International Immunopharmacology,2024,139:[130] Zhang Y, Lei H, Wang P, et al.Restoration of dysregulated intestinal barrier and inflammatory regulation through synergistically ameliorating hypoxia and scavenging reactive oxygen species using ceria nanozymes in ulcerative colitis.Biomaterials Research,2023,27:[131] Zhao H, Zhao H, Li M, et al.Twin defect-rich Pt ultrathin nanowire nanozymes alleviate inflammatory skin diseases by scavenging reactive oxygen species.Redox Biology,2024,70:[132] Wu L, Liu G, Wang W, et al.Cyclodextrin-Modified CeO2 Nanoparticles as a Multifunctional Nanozyme for Combinational Therapy of Psoriasis.International Journal of Nanomedicine,2020,Volume 15:2515-2527[133] Lu X, Kuai L, Huang F, et al.Single-atom catalysts-based catalytic ROS clearance for efficient psoriasis treatment and relapse prevention via restoring ESR1.Nature Communications,2023,14:[134] Yang D, Yuan M, Huang J, et al.Conjugated Network Supporting Highly Surface-Exposed Ru Site-Based Artificial Antioxidase for Efficiently Modulating Microenvironment and Alleviating Solar Dermatitis.ACS Nano,2024,18:3424-3437[135] Cui H, Zhang X, Zhang Z, et al.Killing three birds with one stone: Tumor-membrane-decorated Prussian blue nanovaccines for synergistic management of skin tumors, radiation dermatitis and wounds.Composites Part B: Engineering,2023,264:[136] Xue H, Zeng H, Zhou S, et al.Polydopamine-coated chondroitin sulfate methacryloyl multifunctional microspheres for wound treatment.International Journal of Biological Macromolecules,2024,280:[137] Zhou D, Du M, Luo H, et al.Multifunctional mesoporous silica-cerium oxide nanozymes facilitate miR129 delivery for high-quality healing of radiation-induced skin injury.Journal of Nanobiotechnology,2022,20:[138] He S-B, Shi L-Y, Zheng Q-H, et al.Advances and perspectives of nanozymes in respiratory diseases.Journal of Materials Chemistry B,2023,11:7041-7054[139] Rajasekaran S, Rajasekar N, Sivanantham A.Therapeutic potential of plant-derived tannins in non-malignant respiratory diseases.The Journal of Nutritional Biochemistry,2021,94:[140] Lin S, Cheng Y, Zhang H, et al.Copper Tannic Acid Coordination Nanosheet: A Potent Nanozyme for Scavenging ROS from Cigarette Smoke.Small,2019,16:[141] Shen Q, Cao M, Yu C, et al.Biodegradable Mesoporous Organosilica-Based Nanostabilizer Targeting Mast Cells for Long-Term Treatment of Allergic Diseases.ACS Nano,2024,18:16934-16946[142] Ali S, Sikdar S, Basak S, et al.Label-Free Detection of Epinephrine Using Flower-like Biomimetic CuS Antioxidant Nanozymes.Inorganic Chemistry,2023,62:11291-11303[143] Yang W, Yuan H, Sun H, et al.Co-Mn Complex Oxide Nanoparticles as Potential Reactive Oxygen Species Scavenging Agents for Pulmonary Fibrosis Treatment.Molecules,2024,29:[144] Yin M, Lei D, Liu Y, et al.NIR triggered polydopamine coated cerium dioxide nanozyme for ameliorating acute lung injury via enhanced ROS scavenging.Journal of Nanobiotechnology,2024,22:[145] Yuan R, Li Y, Han S, et al.Fe-Curcumin Nanozyme-Mediated Reactive Oxygen Species Scavenging and Anti-Inflammation for Acute Lung Injury.ACS Central Science,2021,8:10-21[146] Ji H, Zhang C, Xu F, et al.Inhaled Pro‐Efferocytic Nanozymes Promote Resolution of Acute Lung Injury.Advanced Science,2022,9:[147] Liu C, Fan W, Cheng W X, et al.Red Emissive Carbon Dot Superoxide Dismutase Nanozyme for Bioimaging and Ameliorating Acute Lung Injury.Advanced Functional Materials,2023,33:[148] Zou H, Hong Y, Xu B, et al.Multifunctional cerium oxide nanozymes with high ocular surface retention for dry eye disease treatment achieved by restoring redox balance.Acta Biomaterialia,2024,185:441-455[149] Zhang W, Zhao M, Chu D, et al.Dual-ROS-scavenging and dual-lingering nanozyme-based eye drops alleviate dry eye disease.Journal of Nanobiotechnology,2024,22:[150] Zou H, Hong Y, Xu B, et al.Multifunctional Cerium Oxide Nanozyme for Synergistic Dry Eye Disease Therapy.ACS Applied Materials & Interfaces,2024,16:34757-34771[151] Wei W, Cao H, Shen D, et al.Antioxidant Carbon Dots Nanozyme Loaded in Thermosensitive in situ Hydrogel System for Efficient Dry Eye Disease Treatment.International Journal of Nanomedicine,2024,Volume 19:4045-4060[152] Kost O A, Beznos O V, Davydova N G, et al.Superoxide Dismutase 1 Nanozyme for Treatment of Eye Inflammation.Oxidative Medicine and Cellular Longevity,2015,2016:[153] Jiang Z, Liang K, Gao X, et al.Fe-curcumin nanozyme-mediated immunosuppression and anti-inflammation in experimental autoimmune uveitis.Biomaterials Research,2023,27:[154] Jin Y, Cai D, Mo L, et al.Multifunctional nanogel loaded with cerium oxide nanozyme and CX3CL1 protein: Targeted immunomodulation and retinal protection in uveitis rat model.Biomaterials,2024,309:[155] Zhao J, Wang Y, Zhang Y, et al.In Situ Crystallized Ceria‐Vesicle Nanohybrid Therapeutic for Effective Treatment of Inflammatory Intraocular Disease.Advanced Healthcare Materials,2024,[156] Chen Z, Li Z, Tang N, et al.Engineering Ultra‐Small Cerium‐Based Metal–Organic Frameworks Nanozymes for Efficient Antioxidative Treatment of Dry Eye Disease.Advanced Functional Materials,2023,34:[157] Chu D, Zhao M, Rong S, et al.Dual-Atom Nanozyme Eye Drops Attenuate Inflammation and Break the Vicious Cycle in Dry Eye Disease.Nano-Micro Letters,2024,16:[158] Liu S, Bai Q, Jiang Y, et al.Multienzyme‐Like Nanozyme Encapsulated Ocular Microneedles for Keratitis Treatment.Small,2023,20:[159] Yu P, Li Y, Sun H, et al.Mimicking Antioxidases and Hyaluronan Synthase: A Zwitterionic Nanozyme for Photothermal Therapy of Osteoarthritis.Advanced Materials,2023,35:[160] Xiang J, Yang X, Tan M, et al.NIR-enhanced Pt single atom/g-C3N4 nanozymes as SOD/CAT mimics to rescue ATP energy crisis by regulating oxidative phosphorylation pathway for delaying osteoarthritis progression.Bioactive Materials,2024,36:1-13[161] Li Y, Yang J, Chen X, et al.Mitochondrial-targeting and NIR-responsive Mn3O4@PDA@Pd-SS31 nanozymes reduce oxidative stress and reverse mitochondrial dysfunction to alleviate osteoarthritis.Biomaterials,2024,305:[162] Chen Q-W, Cao M-W, Qiao J-Y, et al.Integrated cascade catalysis of microalgal bioenzyme and inorganic nanozyme for anti-inflammation therapy.Nanoscale Horizons,2023,8:489-498[163] Rajasekaran S, Rajasekar N, Sivanantham A.Therapeutic potential of plant-derived tannins in non-malignant respiratory diseases.The Journal of Nutritional Biochemistry,2021,94:108632[164] Wang Y, He X, Huang K, et al.Nanozyme as a rising star for metabolic disease management.Journal of Nanobiotechnology,2024,22:226[165] Gu S, Ran C.Advanced Optical Microscopic Imaging Techniques for Imaging Amyloid Beta and Deciphering Alzheimer’s Disease Pathogenesis.iRADIOLOGY,2025,3:95-114[166] Yang H, Lu D, Liu Z, et al.pH‑responsive nanozyme cascade catalysis: A strategy of BiVO4 application for modulation of pathological wound microenvironment.Journal of Colloid and Interface Science,2024,674:29-38[167] Huang Y, Jia L, Zhang S, et al.Bimetallic doped carbon dot nanozymes for enhanced sonodynamic and nanocatalytic therapy.Journal of Materials Chemistry B,2025,[168] Zhou J, Shi D, Kaneko T, et al.Bioinspired mineralization of ultra-small ceria on cellulose nanofiber enables biocompatible and efficient nanozyme.Carbohydrate Polymers,2025,348:[169] Li H, Liu Z, Zhang P, et al.The recent research progress in the application of the nanozyme-hydrogel composite system for drug delivery.Drug Delivery,2024,31:[170] Han X, Akifumi H, Lv P, et al.Low-Intensity Focused Ultrasound Ameliorates Cisplatin-Induced Cognitive Impairment by Attenuating Hippocampal Neuroinflammation and Enhancing Synaptic Plasticity in Rats.iRADIOLOGY,2025,3:152-167[171] Wang D, Li Q, Xiao C, et al.Nanoparticles in Periodontitis Therapy: A Review of the Current Situation.Int J Nanomedicine,2024,19:6857-6893[172] Liu Q, Zhang A, Wang R, et al.A Review on Metal- and Metal Oxide-Based Nanozymes: Properties, Mechanisms, and Applications.Nanomicro Lett,2021,13:154[173] Dong H, Du W, Dong J, et al.Depletable peroxidase-like activity of Fe(3)O(4) nanozymes accompanied with separate migration of electrons and iron ions.Nat Commun,2022,13:5365[174] Kajarabille N, Latunde-Dada G O.Programmed Cell-Death by Ferroptosis: Antioxidants as Mitigators.Int J Mol Sci,2019,20:[175] Wang Y, He X, Huang K, et al.Nanozyme as a rising star for metabolic disease management.J Nanobiotechnology,2024,22:226[176] Patil U S, Adireddy S, Jaiswal A, et al.In Vitro/In Vivo Toxicity Evaluation and Quantification of Iron Oxide Nanoparticles.Int J Mol Sci,2015,16:24417-50[177] Dai C, Hu R, Cao S, et al.Mesoporous Ternary Nanozymes with Anti-Senescence and Anti-Inflammation Activities for Atherosclerosis Management.Advanced Functional Materials,2024,34:2313646[178] Zhang D, Chen Q, Ren Q, et al.Transition metal-based nanozymes: Classification, catalytic mechanisms and emerging biomedical applications.Coordination Chemistry Reviews,2024,508:215771[179] Younis M A, Tawfeek H M, Abdellatif A A H, et al.Clinical translation of nanomedicines: Challenges, opportunities, and keys.Adv Drug Deliv Rev,2022,181:114083[180] Chen L, Chen S-L, Yuan Y, et al.Complexity made easy: Aggregation-induced emission small molecules for cancer diagnosis and phototherapies.Aggregate,2024,5:e657[181] Chen J, Zheng X, Zhang J, et al.Bubble-templated synthesis of nanocatalyst Co/C as NADH oxidase mimic.Natl Sci Rev,2022,9:nwab186[182] He W, Wu J, Liu J, et al.Single‐Atom Nanozymes for Catalytic Therapy: Recent Advances and Challenges.Advanced Functional Materials,2024,34:[183] Losito D W, Souza N I N, Martins T S, et al.A review of superparamagnetic nanoparticles applications and regulatory aspects in medicine and environmental areas.Journal of Materials Science,2024,59:16038-16068[184] Saravanan N, Ganesh P, Pitchaimuthu S, et al.Nanozyme controlled photothermal heat generation on nanoceria decorated MoS2 nanoflowers for enhanced cytotoxicity in cancer chemo-photothermal therapy.Surfaces and Interfaces,2023,41:103225[185] Wu X, Zhang Y, Xing P, et al.Surface functionalization strategies of ROS-scavenging nanozymes for synergistic therapy and efficient delivery.Journal of Materials Chemistry B,2025,[186] Yu Z, Huang L, Guo J.Anti-stromal nanotherapeutics for hepatocellular carcinoma.Journal of Controlled Release,2024,367:500-514[187] Fury B, Klassen H, Bauer G.Manufacturing of Clinical Grade Cellular Products Under GMP Conditions.Stem Cell Biology and Regenerative Medicine,2019,81-95[188] Zhan H-Q, Zhang X, Chen X-L, et al.Application of nanotechnology in the treatment of glomerulonephritis: current status and future perspectives.Journal of Nanobiotechnology,2024,22:[189] Gibbs J P, Menon R, Kasichayanula S.Bedside to Bench: Integrating Quantitative Clinical Pharmacology and Reverse Translation to Optimize Drug Development.Clinical Pharmacology & Therapeutics,2017,103:196-198[190] Hu Q, Zuo H, Hsu J C, et al.The Emerging Landscape for Combating Resistance Associated with Energy‐Based Therapies via Nanomedicine.Advanced Materials,2023,36:[191] Chen Z, Yu Y, Gao Y, et al.Rational Design Strategies for Nanozymes.ACS Nano,2023,17:13062-13080[192] Wei Y, Wu J, Wu Y, et al.Prediction and Design of Nanozymes using Explainable Machine Learning.Advanced Materials,2022,34:[193] Luo L, Liu Q, Zhang Y, et al.Precisely edited gut microbiota by tungsten-doped Prussian blue nanoparticles for the treatment of inflammatory bowel disease.Journal of Controlled Release,2025,382:113755[194] Huang Q-X, Liang J-L, Yang C-H, et al.Stimulation-responsive mucoadhesive probiotics for inflammatory bowel disease treatment by scavenging reactive oxygen species and regulating gut microbiota.Biomaterials,2023,301:122274[195] Liu Q, Tian J, Liu J, et al.Modular Assembly of Tumor-Penetrating and Oligomeric Nanozyme Based on Intrinsically Self-Assembling Protein Nanocages.Advanced Materials,2021,33:2103128[196] Sun G, Sun K, Sun J.Combination prostate cancer therapy: Prostate-specific membranes antigen targeted, pH-sensitive nanoparticles loaded with doxorubicin and tanshinone Drug Delivery,2021,28:1132-1140[197] Chen Z, Li Z, Tang N, et al.Engineering Ultra-Small Cerium-Based Metal–Organic Frameworks Nanozymes for Efficient Antioxidative Treatment of Dry Eye Disease.Advanced Functional Materials,2024,34:2307569[198] Chen Y, Wang Y, Chen Z, et al.NIR-driven polydopamine-based nanoenzymes as ROS scavengers to suppress osteoarthritis progression.Materials Today Nano,2022,19:100240[199] Xu J, Wu M, Yang J, et al.Multimodal smart systems reprogramme macrophages and remove urate to treat gouty arthritis.Nature Nanotechnology,2024,19:1544-1557[200] Liu Y, Wang B, Zhu J, et al.Single‐Atom Nanozyme with Asymmetric Electron Distribution for Tumor Catalytic Therapy by Disrupting Tumor Redox and Energy Metabolism Homeostasis.Advanced Materials,2023,35:[201] Na L, Fan F.Advances in nanobubbles for cancer theranostics: Delivery, imaging and therapy.Biochemical Pharmacology,2024,226:116341[202] Liu W, Liu D, Liu M.Effects of process parameters on preparation of Ti@SiO2 particles during fluidized bed chemical vapor deposition via design of experiments.Chemical Engineering Research and Design,2022,187:425-433[203] Li H, Huang Y.Expression of brown-midrib in a spontaneous sorghum mutant is linked to a 5′-UTR deletion in lignin biosynthesis gene SbCAD2.Scientific Reports,2017,7:[204] Zhai Y, Pei S, Qin X, et al.Ultralow Dose Iron‐Copper Bimetallic Single‐Atom Nanozymes for Efficient Photothermal‐Chemodynamic Antibacterial and Wound Healing.Advanced Healthcare Materials,2024,14:[205] Zhang R, Jiang B, Fan K, et al.Designing nanozymes for in vivo applications.Nature Reviews Bioengineering,2024,2:849-868[206] Wu X, Guo H, Gao H, et al.Peptide targeting improves the delivery and therapeutic index of glucocorticoids to treat rheumatoid arthritis.Journal of Controlled Release,2024,368:329-343[207] Cheng Y, Zhang Y, Zhao Z, et al.Guanidinium‐Decorated Nanostructure for Precision Sonodynamic‐Catalytic Therapy of MRSA‐Infected Osteomyelitis.Advanced Materials,2022,34:[208] Zhao Q, Wang L, Cheng R, et al.Magnetic Nanoparticle-Based Hyperthermia for Head & Neck Cancer in Mouse Models.Theranostics,2012,2:113-121[209] Tabish T A, Crabtree M J, Townley H E, et al.Nitric Oxide Releasing Nanomaterials for Cardiovascular Applications.JACC: Basic to Translational Science,2024,9:691-709[210] Hou J, Fu R, Yu T, et al.Synergistic antibacterial therapy for multidrug-resistant bacterial infections using multifunctional nanozymes.Nano Today,2024,54:102118[211] Feng Y, Cheng Z, Larsen A-K K, et al.Amyloid-like nanofibrous network confined and aligned ultrafine bimetallic nanozymes for smart antibacterial therapy.Materials Today Bio,2023,22:100730 Information & Authors Information Version history V1 Version 1 24 June 2025 Peer review timeline Published Aggregate Version of Record 15 Sep 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Aggregate Keywords inflammation nanozymes non-neoplastic diseases reactive oxygen species theranostics Authors Affiliations Ling Mei 0000-0002-2762-2235 Chengdu University Sichuan Province Engineering Research Center for Powder Metallurgy View all articles by this author Xikai Wang Chengdu University Sichuan Province Engineering Research Center for Powder Metallurgy View all articles by this author Zhuang Hu Ningbo Hospital of Traditional Chinese Medicine View all articles by this author Jierui Yan Chengdu University of Traditional Chinese Medicine Innovative Institute of Chinese Medicine and Pharmacy View all articles by this author Xiaobo Wang Chengdu University of Traditional Chinese Medicine Innovative Institute of Chinese Medicine and Pharmacy View all articles by this author Haoran Wang Shenzhen MSU-BIT University View all articles by this author Ya Hou Hospital of Chengdu University of Traditional Chinese Medicine Rehabilitation Department View all articles by this author Pengfei Zhang 0000-0003-0390-3806 [email protected] Chinese Academy of Sciences View all articles by this author Qihang Ding 0000-0002-2665-9036 Korea University Department of Chemistry View all articles by this author Metrics & Citations Metrics Article Usage 795 views 357 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Ling Mei, Xikai Wang, Zhuang Hu, et al. Nanozymes for Non-neoplastic Diseases: Catalytic Therapy Redefined. Authorea . 24 June 2025. DOI: https://doi.org/10.22541/au.175072342.22575415/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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