Precision Design of Defect-Engineered MOFs: From Synthetic Strategies to Biomedical Applications

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Data may be preliminary. 13 March 2026 V1 Latest version Share on Precision Design of Defect-Engineered MOFs: From Synthetic Strategies to Biomedical Applications Authors : Xiangkai Qiao 0000-0003-2877-1678 , Jiale Liu , Yifan Pei , Zhen Zhang , Pengyu Dai 0009-0009-6014-0041 , Xinze Hu , MOHAMED SYAZWAN OSMAN 0000-0003-3502-4769 , … Show All … , PAUL SOTO RODRIGUEZ 0000-0002-2425-932X , Dongpyo Kim , Lei Wang 0000-0002-9522-3623 [email protected] , Chunxia Chen , Ding Dai , Sanyang Han , and Tiedong Sun Show Fewer Authors Info & Affiliations https://doi.org/10.22541/au.177339112.24838902/v1 240 views 160 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Metal–organic frameworks (MOFs) as a premier class of crystalline porous materials, celebrated for their architectural precision and vast functional versatility in biomedicine. However, the pursuit of crystalline perfection in pristine MOFs often leads to performance bottlenecks in physiological environments, characterized by rigid active sites, restricted mass transport, and suboptimal loading capacities. Defect engineering, the intentional and precise disruption of framework periodicity has recently ascended as a transformative strategy to transcend these intrinsic constraints. By strategically introducing structural imperfections, such as linker vacancies and cluster modulations, MOFs can be endowed with expanded pore volumes, enhanced surface accessibility, and tailored coordination environments that unlock potential enzyme-like activities. Despite the burgeoning interest in Defect-MOFs, a systematic synthesis of the underlying defect-formation mechanisms and their specialized roles in overcoming the limitations of conventional MOFs in biomedical contexts remains elusive. Drawing the rapid evolution of this field, this review provides a timely and critical deconstruction of the synthesis, structure, performance of Defect-MOFs. We systematically categorize advanced synthetic strategies, highlight representative breakthroughs in targeted drug delivery and synergistic theranostics. Finally, we dissect the pressing challenges regarding reproducibility and biocompatibility, offering a strategic roadmap to inspire the rational design of next-generation, Defect-MOFs nanoplatforms for clinical translation. Cite this paper: Chin. J. Chem. 2025 , 43 , XXX—XXX. DOI: 10.1002/cjoc.70XXX Precision Design of Defect-Engineered MOFs: From Synthetic Strategies to Biomedical Applications Xiangkai Qiao a,§ , Jiale Liu d,§ , Yifan Pei d , Zhen Zhang a , Pengyu Dai a , Xinze Hu a , Mohamed syazwan Osman f , Paul E. D. Soto Rodriguez g , Dongpyo Kim c,* , Lei Wang b,* , Chunxia Chen a,* , Ding Dai a,* , Sanyang Han d,e* , Tiedong Sun a,* a College of Chemistry, Chemical Engineering and Resource Utilization, Northeast Forestry University Harbin 150040, P. R. China b School of Chemistry and Chemical Engineering, Harbin Institute of Technology Harbin 150001, P. R. China c Intelligent Microfluidics for Advanced Theranostics La School of Integrated Circuit, Harbin Institute of Technology, University Town of Shenzhen, Shenzhen, China 518055 d Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University Shenzhen 518055, P. R. China e Key Laboratory of Industrial Biocatalysis, Ministry of Education, Tsinghua University Beijing 100084, P. R. China f EMZI-UiTM Nanoparticles Colloids & Interface Industrial Research Laboratory (EMZI NANO-CORE), Faculty of Chemical Engineering, Universiti Teknologi MARA, Cawangan Pulau Pinang, 13500 Permatang Pauh, Pulau Pinang, Malaysia g Instituto de estudios avanzados IUDEA, Departamento de Física, Universidad de La Laguna C/Astrofísico Francisco Sánchez, s/n.E-38203, Tenerife, Spain § Xiangkai Qiao and Jiale Liu contributed equally. * Corresponding Author: Email： [email protected] MOFs | Modification | Defect engineered | Defect-MOFs | Biomedical Comprehensive Summary Text ：Metal–organic frameworks (MOFs) as a premier class of crystalline porous materials, celebrated for their architectural precision and vast functional versatility in biomedicine. However, the pursuit of crystalline perfection in pristine MOFs often leads to performance bottlenecks in physiological environments, characterized by rigid active sites, restricted mass transport, and suboptimal loading capacities. Defect engineering, the intentional and precise disruption of framework periodicity has recently ascended as a transformative strategy to transcend these intrinsic constraints. By strategically introducing structural imperfections, such as linker vacancies and cluster modulations, MOFs can be endowed with expanded pore volumes, enhanced surface accessibility, and tailored coordination environments that unlock potential enzyme-like activities. Despite the burgeoning interest in Defect-MOFs, a systematic synthesis of the underlying defect-formation mechanisms and their specialized roles in overcoming the limitations of conventional MOFs in biomedical contexts remains elusive. Drawing the rapid evolution of this field, this review provides a timely and critical deconstruction of the synthesis, structure, performance of Defect-MOFs. We systematically categorize advanced synthetic strategies, highlight representative breakthroughs in targeted drug delivery and synergistic theranostics. Finally, we dissect the pressing challenges regarding reproducibility and biocompatibility, offering a strategic roadmap to inspire the rational design of next-generation, Defect-MOFs nanoplatforms for clinical translation. In1989, Robson developed the first MOFs by varying the building blocks, specific substances can be captured and stored inside the cavities. Following pioneering work by Robson, around the turn of the millenium , Kitagawa and Yaghi developed more flexible and stable MOFs, whose highly tunable and coordinatively flexible structure rapidly sparked widespread interest and laid the foundation for this rapidly expanding field of porous materials. In 2006 , Chen pioneered and validated the ligand-directed strategy, laying the foundation for the precise design of subsequent MOFs. In 2007, Bu reported a pcu-type MOF, achieving porosity and defect regulation. By 2008 , Attfield use of atomic force microscopy to reveal surface growth defects in HKUST-1, providing early insight into MOF crystallography defects, while Lillerud introduced the exceptionally stable UiO-66, a zirconium-based framework that later became a cornerstone material in both engineering and biomedical research. In the same year , Wang pioneered the design and regulation of colossal cages in ZIFs for gas storage. In 2009 , Serre pioneered the flexible MIL series and systematically explored framework dynamics (breathing behavior), paving the way for applications in controlled drug delivery and other biomedical fields. A paradigm shift occurred in 2013 when Zhou directly demonstrated and quantified abundant missing-linker defects in UiO-66, establishing defects as a viable and powerful means of property modulation. In 2015 , Fischer formally defined Defect Engineering as a core strategy for precisely tailoring MOF properties. Around 2016 , Morris and coworkers developed effective top-down methods to controllably introduce and manipulate defects, strongly promoting defect-engineered MOFs in drug delivery research. In 2017 , Forgan reported pioneering studies on MOF-based drug loading and controlled release; by 2020 his team achieved a major advance with defect-engineered systems enabling controlled co-delivery of multiple therapeutic agents. In 2018 , Lin and co-wokers harnessed defect sites in nanoscale MOFs to realize highly efficient combination cancer therapy, with their RiMO-301 series becoming one of the earliest defect-engineered MOF platforms to reach clinical trials. In 2019 , Jiang use of defect engineering to improve the catalytic performance of MOFs. In the same year , Zhao and collaborators introduced defect-engineered MOF nanozymes, significantly expanding MOF applications in catalytic nanomedicine, and later innovated asymmetric single-atom catalysis within defect-MOFs for synergistic tumor treatment. In 2020 , Pang reported the introduction of quasi defects, to further enhance the enrichment and catalytic performance of MOFs. In the same year , Shi et al, reported MOF nanozymes for synergistic therapy. In 2021 , Liu’s team developed multifunctional theranostic platforms based on Defect-MOFs that seamlessly integrate imaging and therapy. In 2024 , Ouyang pioneered the development of Defect-MOFs as nucleic acid hydrolase nanozymes. Most recently, in 2025 , Leticia Hosta-Rigau and colleagues demonstrated defect-engineered MOFs for hemoglobin-based oxygen delivery, offering promising new approaches to relieve tumor hypoxia and reprogram the tumor microenvironment. Importantly , Zhao and Li et al. reported the design of MOF-based materials with multiple morphologies, providing a new approach for the design and application of novel Defect-MOFs. Contents 1.Introduction 3 2.Synthesis of defect-engineered MOFs 4 2.1 De novo method 4 2.2. Post-synthesis processing 5 2.2.1. Acid/base post-synthetic 5 2.2.2. Thermal decomposition 5 2.2.3. Solvent-assisted linker exchange (SALE) 6 2.2.4. Recent advanced strategies 7 2.3 Characterization of defect-engineered MOFs 8 2.3.1 Thermogravimetric analysis (TGA) 8 2.3.2 X-ray photoelectron spectrometry (XPS) 8 2.3.3 Raman spectrometry (Raman) 9 2.3.4 Positron annihilation lifetime spectroscopy (PALS) 9 2.3.5 Extended x-ray absorption fine structure (EXAFS) 9 2.3.6 Electron paramagnetic resonance (EPR). 9 3.Defect-engineered MOFs as a delivery carrier 9 3.1. Drug delivery 9 3.2. Enzyme immobilization and delivery 10 4.Defect-engineered MOFs for enhanced tumor Theranostics 11 4.1. Defect-engineered MOFs for enhanced tumor marker detection and diagnosis 11 4.2. Defect-engineered MOFs for enhanced radiotherapy 12 4.3. Defect-engineered MOFs for enhanced sonodynamic therapy 12 4.4. Defect-engineered MOFs for enhanced immunotherapy 12 4.5. Defect-engineered MOFs for enhanced Photo-/Chemo- dynamic therapy 13 4.6. Defect-engineered MOFs for enhanced photothermal therapy 13 4.7. Defect-engineered MOFs for all-in-one therapeutic 14 5.Conclusion and outlook 15 6. Ackonwledgement 16 7. Dedication 16 1. Introduction Metal-Organic Frameworks (MOFs), defined as highly ordered porous crystalline materials constructed from metal nodes and organic linkers via coordination bonds, have rapidly become a central focus in materials science since their initial report by O. M. Yaghi in 1995. [1] Due to their characteristics such as high specific surface area, tunable pore structures, and functional sites, they exhibit broad application prospects in fields like gas storage, separation, catalysis, sensing, and energy. [2-5] Furthermore, benefitting from their controllable structural design and physicochemical stability, MOFs have demonstrated significant potential in biomedical applications. [6-11] However, despite their enormous potential across various applications, traditional MOFs still face formidable challenges that impede their widespread adoption and clinical translation. [12-14] The primary limitations stem from inherent issues regarding their stability, biocompatibility, and functional regulation. For instance, some traditional MOFs suffer from structural collapse and disintegration in aqueous or physiological environments, leading to premature drug release or the leakage of toxic metal ions. [10, 15, 16] Concurrently, conventional synthesis methods often result in material issues such as easy aggregation, poor scalability, limited ligand variety, and difficulty in precise pore regulation, [17-20] cannot achieve efficient drug transport and controlled release, causing systemic side effects or insufficient overall efficacy. These problems not only affect the clinical translation of MOFs but also hinder their application potential in combination therapy. To overcome these limitations, the construction of Defect-engineered MOFs (Defect-MOFs) emerged as an effective strategy. By introducing structure modulation to intentionally create missing-linker or missing-node defects within the framework Fig. (2) , additional open metal sites can be generated, thereby significantly enhancing drug loading capacity and catalytic activity. Lillerud et al, [21] reported the defects in the UiO-66 system, confirming their role in drastically improving porous properties. Fischer et al. [22, 23] further systematized the concept of defect engineering, demonstrating how to precisely manipulate these active sites using synthetic modulators to enhance performance. Defect-engineered allows for the precise regulation of MOFs structures without compromising overall framework integrity.[24-26] Furthermore, the open sites provided by these defects endow MOFs with nanozyme catalytic activity, while offering more loading positions for other functional molecules. Fig. 2. Schematic of Defect-MOFs, including ligands defects and metal node defects. Structural modulation in Defect-MOFs facilitates band gap engineering and framework reconstruction, notably improving stability in acidic tumor environments. Based on this, strategies have emerged to further tune these properties. [27-31] Forgan et al, [27] employed a multivariate modulation strategy to simultaneously load up to three therapeutic agents into the defect sites of a Zr-MOF (UiO-66), validating defect engineering’s potential to enhance multi-drug loading capability. Wang et al, [28] further improved the drug-loading capacity of UiO-66-NH2 by over twofold through ligand deficiency and the introduction of a BDC-NH2 modulator that competes for Zr coordination. Recently, Deshmukh and Morris, [32] further refined the control of defect landscapes through a multivariate (MTV) approach. This transition from static defect engineering to stimuli-responsive functional modulation marks a pivotal evolution, elevating simple drug carriers into sophisticated, on-demand drug release platforms. Crucially, defect engineering not only overcomes the limitations of conventional MOFs in drug delivery and biocompatibility but also endows them with enzyme-mimicking (nanozyme) catalytic activity, [33-38] enabling catalytic tumor therapy and mitigating oxidative stress. Lin et al, [39] eveloped Ti-based Defect-MOFs capable of efficient ultrasound-triggered reactive oxygen species (ROS) generation, achieving synergistic sonodynamic (SDT) and chemodynamic (CDT) therapeutic effects for pronounced tumor inhibition. In 2024, Ouyang et al, [40] reported a reo-type cluster-missing UiO-66 nanozyme. By leveraging its unique defective boundaries, they achieved efficient phosphodiester bond cleavage under physiological conditions, offering a new paradigm for Nanozyme. In 2025, Liu et al, [34] designed Defect-MOFs nanoscale platforms with strong self-assembly enzyme activity through defect engineering, achieving precise targeting and oxidative stress treatment. In addition, advanced platforms, such as Defect-MOF-based nanomotor-integrated therapeutic systems, are being widely explored to facilitate deep-tissue tumor diagnosis and therapy. [41, 42] Fig. 3. This scheme illustrates the evolution from MOFs to Defect-MOFs, highlighting key milestones and advancements in Defect-MOFs over time, from engineering to biomedical applications. Reproduced with permission. [43] Copyright © 2004, Macmillan Magazines Ltd. Reproduced with permission. [21] Copyright © 2008, American Chemical Society. Reproduced with permission. [44] Copyright © 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. Reproduced with permission. [45] Copyright © 2012, American Chemical Society. Reproduced with permission. [46] Copyright © 2013, American Chemical Society. Reproduced with permission. [47] Copyright © The Royal Society of Chemistry 2015. Reproduced with permission. [48] Copyright © 2017, Springer Nature. Reproduced with permission. [49] Copyright © 2020, American Chemical Society. Reproduced with permission. [35] Copyright © 2021 Wiley‐VCH GmbH. Reproduced with permission. [50] Copyright © 2025 Wiley‐VCH GmbH. Over the past 30 years since MOFs were first proposed, Fig. 3. Defect-MOFs have attracted extensive research interest in diverse fields, including resource and environmental science, as well as biomedicine. [51-53] However , despite the extensive studies demonstrating that defect engineering significantly enhances the drug delivery and therapeutic performance of MOFs, a comprehensive and systematic review specifically focusing on the biomedical applications of Defect-MOFs remains scarce. Furthermore , systematic analyses of their design principles under complex biological environments and the underlying mechanisms by which defects influence their biomedical behavior are still limited. Therefore , this review aims to provide a timely and systematic summary of the latest advances in this rapidly emerging field. We will highlight representative examples to elucidate these mechanisms and underscore the great potential of Defect-MOFs in biomedical applications. This review is structured around the following key aspects: (i) Synthesis and characterization strategies of Defect-MOFs. (ii) The unique structural designs and defect-driven mechanisms for improved biomedical performance. (iii) Current challenges and future perspectives in their rapid synthesis and ultimate biomedical translation, with the goal of providing insights for the further development of Defect-MOFs in this promising field. 2. Synthesis of defect-engineered MOFs Defect engineering is an exciting concept for material properties, heterogeneity, structural disorders, and defects of various nature and length scales are key attributes of the materials and strongly affect their physical and chemical properties. [22] Defects are not random but result from rational design, such as introducing modulators, (e.g., ligand and metal node defects) that alter the coordination between metal centers and organic linkers. [37] The primary synthesis method for medical Defect-MOFs are the de novo method and post-synthetic modification, as shown in Fig. 4. Fig. 4. Schematic illustration of the synthetic routes of Defect-MOFs include De novo method and Post-synthesis processing, among which: (i) Ion substitution (ii) Acid etching, (iii) Thermal decomposition, (iv) Solvent-assisted linker exchange. 2.1. De novo method De novo synthesis entails intentionally incorporating defects into MOFs by varying precursors Fig. 5(A) and reaction environments. [54] Consequently, Defect-MOFs formed through this approach can also be defined as MOFs with mixed linkers, [55] For instance, Xiong et al, [56] synthesized MOFs with mixed linkers by dissolving ligands in methanol and adding Zn 2+ solution, creating linker defects without requiring proton-removal agents. Fig. 5(B). Similarly, Åhlén et al, [57] found that adjusting the ligand mixing ratio could customize the particle size and pore size of the Defect-MOFs, thereby altering their adsorption capacity. Fig 5. (A) Representative ligands in the synthesis of Defect-MOFs. (B) Synthesis of ZIF-8-NH 2 via de novo synthesis. [55] Copyright © 2024 Elsevier B.V. (C) A schematic illustration of the fabrication procedure for metal SACs through the defect engineering strategy in MOFs. [58] Copyright © 2021 Wiley-VCH GmbH (D) Imaginative Diagram of the Formation Process of Ti-BDC-A. [59] Copyright © 2020 American Chemical Society (E) The Schematic illustration for pristine NH 2 -UiO-66 and defective SS-NH 2 -UiO-66-X. [60] Copyright © 2022 Elsevier B.V. In the de novo, monocarboxylic acids and their salts are used to interfere with linker coordination, also enhancing defect concentration. [44, 61] For instance, Wang et al, [62] investigated the varying ratios of modulator (formic acid, FA) to linker (2-aminotriacetic acid) and reaction time affect the defect size in UiO-66 derivatives. In addition, similar to the capping effect, H 2 O molecules can also be coordinated with metal clusters to stabilize the framework and free carboxyl groups. Modulated by benzoic acid, He et al [22, 58] , synthesized a series of defect-engineered PCN-222 MOFs with Co-TCPP linkers, later converting them into single-atom catalysts through pyrolysis Fig. 5(C) , In this work, the input ratio of H 2 O and benzoic acid directly determined the defect size, which expanded the spatial distance between the linkers. In another research, Ye et al, [59] added acetic acid to a mixed Ti 4+ and BDC (benzene dicarboxylate) solution, causing some linkers to detach. As shown in Fig. 5(D) , this exposed active sites, enhancing the catalytic performance of Ti-BDC. Recent studies have also explored delayed addition of modulators, which allows them to interact with already-formed MOFs, altering the coordination state of metal clusters or linkers. This approach is akin to post-synthesis treatments. For example, Li et al, [60] found that adding vignette salt to NH 2 -UiO-66 composed of Zr and BDC-NH 2 removed certain metal clusters, creating oxygen vacancy defects Fig. 5(E). Furthermore, Tao et al, [63] leveraged Fe(NO 3 ) 3 as a modulator, capitalizing on Fe 3+ affinity for BDC, to induce defects in F-MOF-808. This generated numerous adsorption sites and optimized pore structures, resulting in improved adsorption capacity (305.5 mg/g) and rapid diffusion (37.51 mg/g⋅min 0.5 ), surpassing the pristine MOF-808 performance. These examples demonstrate that de novo method allows precise control defect formation. By adjusting the modulator type, amount, and timing of introduction, researchers can fine-tune MOFs structural properties for targeted applications. However, the stochastic distribution of ligands in multivariate systems hinders the precise synthesis of specific defects. To address this challenge, Feng et al. [64] utilized a crystallographically ordered framework to achieve site-specific defect incorporation and revealed the correlation between defects and catalytic efficiency, defining the structural limits of the framework. 2.2. Post-synthesis processing Post-synthesis refers to introducing defects by some severe means after the successful synthesis of parent MOFs that conform to the desired structure [23, 65, 66] . For example, metal ion substitution in the MOFs, due to the different coordination of those two metal ions, so the number of linkers between the center ions and organic ligands. As a result, more functional groups, such as hydroxyl and amino groups, are exposed for reaction. This method may allow the radius of the second ion to be smaller than the center ion. [65] Meanwhile, thermal defect engineering is a unique process in the post-synthesis of Defect-MOFs, [66] it can create the defect in MOFs without the choice of nodes, linkers, and topology. Fig. 4 illustrates post-synthesis preparation of Defect-MOFs, followed by defect formation through (i) Ion substitution (ii) Propionic acid etching, (iii) Thermal decomposition, (iv) Solvent-assisted linker exchange. 2.2.1. Acid/base post-synthetic. The acid/base post-synthetic strategy, also known as etching method. involves replacing or protonating the organic ligand, and even completely dissolving the specified linker. To etch away the original linker, this strategy may require MOFs precursor immersed into acid/base. [67, 68] Ligand competition triggered by different pKa values may lead to the formation of these defects. While this approach is effective for removing specified linkers under specific pH conditions to create linker defects, cluster defects, or even mesoporous defects, particular attention should be paid to the structural changes of drug molecules at different pH levels when loading drugs using this strategy, as this may dramatically affect efficacy. Innovatively, Yuan et al, [48] constructed uniquely customized pores in MOFs using solvent-assisted ligand incorporation methods, Fig. 6(A) shows the synthesized method of Zr-AZDC-MOFs (PCN-160), each Zr 6 cluster connected by 12 AZDC . To achieve suitable pore structures in the Defect-MOFs, the ligand of CBAB (4-carboxybenzylidene-4-aminobenzate), was reacted in DMF solution at 75°C. During the ligand exchange of CBAB, the reduced coordination of metal clusters leads to the removal of the Zr 6 cluster and the linked ligands, forming mesopores of about 2.5 nm as illustrated in Fig. 6(B) . It was demonstrated that the defect concentration could be controlled by adjusting the exchange ratio and acid concentration. Similarly, Yang et al, [69] treated activated UiO-66 with acids of different carbon chain lengths, and MOFs etched with less acidic acetic, propionic, and butyric acids retained the original octahedral crystal structure. As shown in Fig. 6(C) , with decreasing acidity, propionic acid (pKa = 4.87) had the weakest affinity for Zr-O clusters, leading to uniformly distributed mesopores. Fig. 6 (A) Hierarchically porous MOF developed by linker labilization. (B) Formation mechanism of the micropores, small mesopores. [48] Copyright © 2017. (C) The overall etching process indicates the formation of hierarchical pores. [69] Copyright © 2018 Wiley-VCH Verlag GmbH & Co. 2.2.2. Thermal decomposition. Thermal decomposition can create defects by removing the template molecules in MOFs without the need to select nodes, linkers, or topology. Science the synthesis temperature and calcination environment influence the coordination state of metal clusters, calcination at different temperatures or annealing at a specific values (e.g., framework decomposition temperature) can eliminate some ligands, eventually forming more open frameworks with free coordination sites and intact external structures. [70, 71] However, random defects sometimes lead to uncontrollable structures. To address the challenge of defect dispersion, Meng et al, [72] synthesized the Pt@UiO-66-NH 2 with hierarchical pores by calcining at 250°C for 2 h. As shown in Fig. 7(A), the decarboxylation and deamination during annealing resulted in the formation of 3.6 nm defects in the MOFs. By adjusting of annealing temperature, a series of MOFs with hierarchical pore defects were prepared. Feng et al [73] , proposed a general defect-generation strategy involving linker pyrolysis. The thermally destructible linker 2-amino-1,4-benzenedicarboxylate (BDC-NH 2 ) was used to synthesize multifaceted MOFs, and by controlling the decomposition temperature (325°C), the thermosensitive linker was selectively removed, resulting in the formation of unsaturated metal clusters, as illustrated Fig. 7(B) . Thermodynamically driven clusters undergo aggregation, eventually form large scale defects, which can also be explained by Ostwald ripening. Thus, differences in thermal stability between ligands serve as a gateway to creating defect-engineered MOFs, with precise temperature control being crucial. The difference in thermal stability of various linkers demonstrated in Fig. 7(C), revealing the thermal stability of the corresponding frameworks, which would facilitate the pyrolytic synthesis of more multicomponent MOFs. Similarly, according to Xu et al, [74] achieved graded porous HP-UiO-66 by removing BDC-NH 2 from UiO-66 with mixed ligands (BDC and BDC-NH 2 ) at 350°C Fig. 7(D) . This thermal decomposition created additional pores, resulting in an ultrahigh adsorption capacity of 248.75 mg/g under neutral conditions. However, high-temperature pyrolysis may degrade the intrinsic properties of MOFs. To address this, Pan et al, [75] proposed a mid-temperature calcination strategy. Briefly, MIL-101 underwent temperature-dependent dimensional shrinkage during calcination at 200°C, reflecting microscopic lattice contraction. Partial ligand bond breakage created metal cluster defects, enhancing the formation of catalytically active sites, and then calcination at 280°C resulted in a tenfold increase in oxidation activity. As shown in Fig. 7(E) , the argon adsorption isotherm revealed secondary absorption, confirming the presence of micro- and mesoporous-like defects. Fig. 7 (A) Schematic illustration of hierarchically porous Pt@MOFs prepared by inherent defects for high catalytic efficiency. [72] Copyright © 2018 WILEY-VCH Verlag GmbH & Co. (B) Zr 6 O 4 (OH) 4 (CO 2 ) 12 clusters are transformed into decarboxylated Zr 6 O 6 clusters after linker thermolysis, and they tend to aggregate with the assistance of oxygen species, forming ultrasmall MO nanoparticles eventually. Overall, the microporous MTV-MOF, UiO-66-NH 2 -R%, is converted into ultrasmall MO@HP-MOF composites through controlled linker thermolysis. (C) Versatility of linker thermolysis to construct HP-MOFs with various linkers. [73] Copyright © 2018 American Chemical Society. (D) Schematic of the HP-UiO-66 synthesis procedure and arsenate adsorption. [74] Copyright © The Royal Society of Chemistry 2020. (E) Schematic illustration for the structural evolution of MIL-101 under thermal treatment in a medium-temperature range. Ar sorption isotherms for pristine MIL-101 and calcined MIL-101. Open symbols represent the desorption branches. The inner illustration shows the pore size distributions of the corresponding samples. [75] Copyright © 2020 WILEY-VCH Verlag GmbH & Co. 2.2.3. Solvent-assisted linker exchange (SALE). SALE, this method is straightforward and efficacious, transcending the inherent limitations of the MOFs topology, and addressing the fundamental challenge of forming defective structures that cannot be formed through de novo synthesis. The primitive ligands of MOFs undergo component substitution in a specific solvent, including metal atom substitution and linker substitution. This strategy can also be further improved to eliminate the defects of unintended ligands, facilitating the construction of metal node defects. [76-78] A comprehensive overview of the progress has been presented by Karagiaridi et al. [79] Fig. 8(A) illustrated the SALE can be used as a heterogeneous reaction of the parent MOFs with a concentrated solution of the cargo (metal atoms or linkers), where the cargo is immobilized within a framework that retains the parent crystal topology. Precious linkers and quantitative synthesis are particularly suitable for this strategy, as the solubility hindrance of the linkers can be overcome with an appropriate solvent. Additionally, SALE facilitates the control of chain reactions and changes in reactivity. To improve the catalytic activity by reducing the oxidation potential of Zr 6 clusters, it can be observed in Fig. 8(B). Lee et al, [47] constructed UiO-66 derivatives with mixed metal atoms and linkers using SALE. The titanium ions dissolved in DMF replaced part of the Zr 6 cluster, and the secondary structural unit could thus accept the electrons generated by the absorption of light by the linker. They also replaced the original linker partially with 2,5-diaminobenzene-1,4-dicarboxylic acid, which broadened the light absorption range, as a result, the MOFs 1(Zr/Ti) has large nano scale than UiO-66(Zr/Ti)-NH 2 meanwhile, the photocatalytic efficiency of MOFs 1(Zr/Ti) also higher than UiO-66(Zr/Ti)-NH 2 . As shown in Fig. 8(C). Son et al, [80] first proposed a general scheme for SALE-based ceriu m MOFs, where methanol facilitated the partial replacement of terephthalic acid with 2-aminoterephthalic acid or 2-hydroxyterephthalic acid. This strategy is reproducible for commonly used BDC derivatives, and the catalytic activity is further enhanced by the substituted linker and the valence of Ce. Karagiaridi et al, [77] reported a method for introducing exposed carboxyl groups in MOFs, where the NU-125 derivative with isophthalate as a linker undergoes linker exchange in DMF containing conjugate base of trimesic acid (H 3 BTC), where Cu 2+ can provide only two ligand nodes, allowing H 3 PTC to carry a free carboxyl group Fig. 8(D). In conclusion, SALE has created Defect-MOFs by linker exchange of the perfect MOFs under varying conditions (temperature, acidity, etc.) and modifying as wishes. Fig. 8 (A) Schematic representation of the incorporation of longer linkers into a MOF through SALE. [79] Copyright © 2014 WILEY-VCH Verlag GmbH & Co. (B) Synthesis of mixed-ligand MOF 1(Zr) via PSE to obtain mixed metal MOFs 1(Zr/Ti), UiO-66(Zr/Ti)-NH 2 . [47] Copyright © The Royal Society of Chemistry 2015. (C) A facile solvent-assisted linker exchange procedure was developed to functionalize Ce-UiO-66 with amine and hydroxyl groups to produce MOFs that were unachievable via de novo methods [80] Copyright © The Royal Society of Chemistry 2020 . (D) Idealized Representation of the Synthesis of NU-125-HBTC by SALE of IPA for HBTC in NU-125-IPA. [77] Copyright © 2015 American Chemical Society. 2.2.4. Recent advanced strategies. It is essential to explore the conditions affecting defect formation, as this will promote more rational strategies for synthesizing Defect-MOFs, leading to more controllable, rapid, and rational results. This section summarizes the defect construction techniques that have emerged in recent years. (1) Plasma Method: Linkers in MOF crystals can be removed by bombardment with highly reactive species, such as ions and free radicals. Xiang et al, [81] decomposed some of the linkers from UiO-66 in a dynamic argon plasma atmosphere, adjusting the defect concentration by varying the plasma treatment time Fig. 9(A) . They found that the number of linker deficiencies on the UiO-66 per Zr 6 cluster could reach up to 2.3 after 30 minutes of argon plasma treatment, resulting in improved CO 2 capture and utilization in Defect-UiO-66. This method operates under atmospheric pressure and near room temperature, making it highly energy-efficient and environmentally friendly. (2) Photolysis Method: The simultaneous presence of excited electrons and intense energy generated by a laser can break “photolabile” linkers, selectively removing ligands and enlarging the cavities of MOFs. In Fig. 9(B). Wang et al, [82] used this photolysis strategy to eliminate TCPP in UiO-66 with mixed ligands, retaining the robust BDC. The defect and mesopore size can be controlled by varying the UV irradiation time and the ratio of linkers. Remarkably, this process takes only ten milliseconds, allowing precise regulation of the form and number of defective structures in UiO-66. (3) Electrosynthesis method ：Protons in the linker can be eliminated through redox reactions occurring in an electrolytic cell, with the dehydrogenated linker coupling with metal ions in the electrolyte to create linker defects. The templated electrosynthesis technique proposed by Kang et al, [83] constructs defects in MOFs within 100 seconds. They used copper foil as a cathode to replenish Cu 2+ in the electrolyte (OmimBF4) solution, leading to coordination with the deprotonated linker biphenyl-3,3’,5,5’-tetracarboxylic acid, which resulted in uncoupled Cu 2+ in the parent MOFs that could serve as Lewis acid sites Fig. 9(C) . The structure of the defects and the porosity of the MOFs can be determined by energy input and linker content. (4) Machine Learning-Assisted: By exploiting the modularity of MOFs, ML-based high-throughput screening significantly narrows down the vast library of linker-metal combinations in a fraction of the time Fig. 9(D) . [84] This methodology streamlines the ligand exchange process, effectively reducing synthetic failures and facilitating the targeted fabrication of Defect-MOFs. (5) In situ catalytic etching: Beyond above methods, a novel in situ catalytic etching strategy has recently emerged. [85] Unlike conventional de novo or post-synthetic treatments, this self-enhancing mechanism attribute to the self-enhanced POD-like activity induced by in situ defect engineering, offering a pioneering perspective on autonomous defect engineering. Fig. 9 (A) Schematic illustration of the preparation of defective UiO-66 via argon plasma bombardment. [81] Copyright © 2020 Elsevier Ltd. (B) The experimental process of photolysis on UiO-66-TCPP. [82] Copyright © 2020, John Wiley and Sons. (C) The schematic diagram for the electrosynthesis of MFM-100. [83] Copyright © 2019. (D) Machine Learning-Assisted Exploration of Chemical Space of MOF-5. [84] Copyright © 2025 Wiley – VCH GmbH. In conclusion, these structural vacancies optimize pore environments, micropores enhance substrate selectivity, while hierarchical mesopores facilitate mass transport in advanced catalysis, such as in situ Fenton-like reactions. Among synthetic strategies (Table 1) , the de novo modulator-assisted approach excels in fine-tuning defect concentrations, specifically, it facilitates the production of well-dispersed nanomedicines when drugs serve as compensating ligands. Alternatively, post-synthetic methods like acid/base etching provide extensive porosity but are constrained by the pH-sensitivity of biological environment. While thermal decomposition yields open frameworks with accessible active sites, it often introduces structural randomness. Finally, Solvent-Assisted Ligand Exchange (SALE) overcomes topological constraints to access defective structures unreachable via de novo routes. Despite this progress, balancing crystal growth kinetics with linker solubility remains a critical challenge. Table 1. Synthesis of Defect-MOFs and improvement the properties. ZIF-8 Ligand Substitution De novo Separation [56] ZIF-8 Ligand Substitution De novo Selectivity and adsorption [57] UIO-66 Missing ligand or metal clusters De novo High specific surface areas [44, 61] PCN-222(Co) Missing ligand De novo single-atom catalysts [22, 58] MIL-125(Ti) Missing ligand De novo Abundant active sites [59] UiO-66 Missing ligand and metal clusters De novo Vacancy and stratified pore [60] Zr-MOFs Missing ligand Post-synthesis Adsorption and catalysis [48] UiO-66 Ligand Substitution Post-synthesis Enzyme adsorption [69] UiO-66 Missing ligand and metal clusters Post-synthesis Dynamic selectivity [72] HP-MOFs Missing ligand Post-synthesis Adsorption and catalysis [73] UiO-66 Missing ligand and metal clusters Post-synthesis Adsorption and catalysis [74] MIL-101 Missing ligand Post-synthesis Catalytic activity [75] UiO-66 Ligand Substitution Post-synthesis Photocatalytic [47] UiO-66 Ligand Substitution Post-synthesis Catalytic activity [80] NU-125-IPA Ligand Substitution Post-synthesis High-density defect-engineered [77] UiO-66 Missing Ligand Post-synthesis Catalytic activity [81] UiO-66 Missing metal Post-synthesis Sensing and catalysis [82] Cu-H4L Missing Ligand Post-synthesis active sites for catalysis [83] UiO-66 Missing ligand Post-synthesis Green defect construction [86] 2.3. Characterization of defect-engineered MOFs Fig 10. (A). TGA curves of UiO-66 (Zr) samples grown for: 2 h, 4 h, 8 h, 24 h, 48 h and 72. [88] Copyright © 2015 Elsevier Ltd. (B). XPS spectrum of Zn 2p. [89] Copyright © 2023 Elsevier B.V. (C). Raman spectra of Ni/MOFDC and AT-Ni/MOFDC (the inset shows a typical deconvoluted Raman signal of carbon). [90] Copyright © 2020 American Chemical Society. (D). Positron annihilation lifetime spectra for MIL-101-Cr, MIL-53-Al and ZIF-8. [91] Copyright © 2020 Elsevier Inc. (E). EXAFSk3χ(k) Fourier transform (FT) spectra of Ni-MOF and D-Ni-MOF. [92] Copyright © 2020 Wiley-VCH GmbH. (F). EPR spectra were measured at room temperature. [93] Copyright © 2020 Elsevier B.V. 2.3.1. Thermogravimetric analysis (TGA). Thermogravimetric analysis (TGA) measures the mass change of MOFs as a function of temperature, providing valuable insights into the composition of intermediate products and the thermal stability during decomposition. Data from TGA, recorded in thermogravimetric curves, are obtained through a relatively simple and quick process, making TGA one of the most widely used methods for studying defects in MOFs. In particular, thermogravimetric curves can help identify connector defects in MOFs. Defect-engineered MOFs often exhibit a significantly lower weight loss than theoretically expected during thermal decomposition. By comparing thermograms of structurally intact and defect-engineered MOFs, researchers can estimate the approximate percentage of connector defects. Thus, TGA, through straightforward principles and calculations, provides structural information on MOFs with non-stoichiometric components and can support hypotheses about gaps in the framework. Ren et al, [88] utilized TGA to study connector defects in UiO-66. As shown in Fig. 10(A) , they used the mass at 300°C, following dehydration, as the dry mass of the ideal UiO-66 structure. In their TGA measurements, benzene mass loss from the linker was clearly defined. With increasing synthesis time (from 2h to 24h), coordination competition led to more modulators replacing the original linker terephthalic acid, which resulted in an increased relative weight loss. While TGA provides preliminary evidence for defects in many studies, it is limited in identifying specific defect types (such as metal cluster or connector defects), which restricts detailed explanations of reaction mechanisms. Therefore, additional qualitative equipment is required, such as TGA-MS. This combined technique introduces the molecular weight of gaseous products from the thermogravimetric analyzer into a mass spectrometer, enabling qualitative and quantitative characterization that is highly suitable for identifying defect types in defect-engineered MOFs. 2.3.2. X-ray photoelectron spectrometry (XPS). XPS, which involves using monochromatic light to produce photoelectric effects that are recorded as electron-binding energy spectra, is a crucial tool for investigating the elemental composition and ionic states in the surface layers of materials, providing essential surface chemical information. Defects in MOFs alter binding energies, leading to shifts or new peaks in the spectra, which can indicate linker elimination or substitution. By analyzing shifts and peak area changes, researchers can preliminarily deduce the formation of defective structures. Numerical changes in binding energy offer in-depth insights into defect content and coordination. New peaks, indicating novel coordination relationships, may suggest metal atom doping or the presence of multiple linkers. Xiang et al, [89] used XPS to analyze coordination states in defect-engineered ZIF-L, focusing on characteristic peak shifts related to defects in Zn clusters. In Fig. 10(B) , the Zn 2p1/2 and Zn 2p3/2 orbitals correspond to binding energies of 1045.0 eV and 1021.9 eV, respectively. Acid etching eliminated certain linkers around Zn, increasing the electron density of the unsaturated Zn 2+ , which led to a 0.2 eV shift to lower binding energy. 2.3.3. Raman spectrometry (Raman). Raman spectroscopy, a scattering spectroscopy, is widely used to study molecular structures by providing information about molecular vibrations and rotations, including vibrational energy levels. It complements infrared spectroscopy and relies on vibrational energy changes in chemical bonds, reflected in Raman shifts associated with lattice vibrational modes of MOFs. Defects such as doping and vacancies in MOFs lead to variations in Raman shift, peak intensity, or the appearance of new peaks. Mofokeng and co-workers, [90] constructed oxygen vacancy defect-engineered Ni-MOF (AT-Ni/MOFDC) by carbonization and acid treatment. In Fig. 10(C). Raman spectra show the characteristic peaks (487 cm -1 ) corresponding to the vibrations of the Ni-OH coordination bond and the newly formed D, G, and 2D bands. after etching by acid treatment, the characteristic peak of Ni-OH becomes flat, While the 2D band (2450 cm -1 ) remains stable, this indicates the elimination of Ni 2+ and the formation of defects. Subsequently, these feature peaks were used for spectral fitting and exhibited five feature bands. The calculated I D1/ I G values of the defect-engineered MOFs exhibited an increase, which can be attributed to the presence of defects. 2.3.4. Positron annihilation lifetime spectroscopy (PALS). PALS uses positrons to analyze porosity, annihilating upon electron interaction and releasing gamma rays. In recent years, PALS has become essential in nuclear physics and materials science for studying grain interfaces and interfacial defect distributions, identifying vacancy defects with high sensitivity. For defect-engineered MOFs, PALS provides information on crystal structure, microscopic defects, charge density distribution, and electron momentum density. Detectable defects include microvoids at intersections and large voids within the crystalline structure, aiding in new material identification. Zhang et al, [91] applied PALS to investigate MOF defect structures. In Fig. 10(D) , the electron lifetime spectrum was decomposed into multiple components using the LT program, with τ 3 fixed between 1.95-2.53 ns, representing positron lifetimes within crystal defects. Their findings revealed that methyl orange adsorption occurred primarily near defects of complex, unsaturated metal clusters in MIL-101-Cr and MIL-53-Al, with calculated aperture sizes suggesting vacancy defects. 2.3.5. Extended x-ray absorption fine structure (EXAFS). EXAFS is widely used to study atomic structures in crystalline and amorphous materials, offering information on local environments and electronic structures. This technique focuses on short-range order and complements diffraction methods. EXAFS provides atomic arrangement ”fingerprints,” enabling researchers to assess coordination structure consistency. Parameters like atomic spacing, coordination numbers, and valence states can be derived, which help identify defects in defect-engineered MOFs. Zhou et al, [92] found that intact and defect-engineered Ni-MOFs both displayed a main peak at 1.60 Å, related to Ni-O coordination. Fig. 10(E) indicates that the coordination number in defect-engineered MOFs was lower than in pristine MOFs, suggesting that connector elimination resulted in unsaturated metal clusters and oxygen vacancies. 2.3.6. Electron paramagnetic resonance (EPR). The electron spin is coupled to non-quantum electromagnetic vibrations and emits energy along with the resonance, which is defined as paramagnetic resonance. This feature is related to the internal structure and composition of the material and is also used to analyze the interactions between substances. EPR focuses on unpaired electronic states in compounds, which is used to study the properties of the environment surrounding electrons. The EPR results reflect the signals of oxygen vacancies, which are closely related to the defect sites in MOFs. Also, the strength of the EPR signal reflects the content or size of the defect. The absence of metal atoms causes defects in atoms containing single electrons, and connector elimination results in oxygen vacancies, Therefore, for defect-engineered MOFs, EPR mainly exhibits interactions between unpaired electrons in the lattice. Wang et al, [93] examined connector defects in MIL-88 with varying defect levels via EPR. As shown in Fig. 10(F). A characteristic signal (g = 2.00), is present in all defect-engineered type MIL-88 (Fe), and shows that it has a unified structure. Signals of three different ligand-substituted MIL-88(Fe) were broadened significantly. The characteristic peak intensity of Bac-MIL88(Fe), Py-MIL88(Fe), and Pca-MIL88(Fe) were enhanced, reflecting elevated levels of linker defect. According to the analysis, the pyrrole in Pca increases the electron density of the carboxyl group, and this asymmetric coordination induces larger defect sizes. 3. Defect-engineered MOFs as a delivery carrier MOFs are recognized as versatile delivery platforms, particularly in biomedicine, owing to their high surface area, tunable structures, and well-defined porosity. [94] Since the pioneering work by Férey et al. in 2006, [95] which first utilized MOF cavities for anticancer drug delivery, various strategies including in situ encapsulation, electrostatic adsorption, and covalent conjugation have been extensively reported for loading therapeutic agents and enzymes. [38, 96-98] However, the diffusion of guest molecules is often hindered by the inherent lattice constraints of microporous MOFs. Furthermore, the robust non-covalent interactions between the framework and cargo pose significant challenges for achieving both high loading capacity and controlled responsive release. [99, 100] Defect engineering offers a transformative solution by altering the molecular architecture of the crystals to modulate intramolecular forces, thereby facilitating efficient loading and release kinetics. [101] In this section, we systematically review the application of defect-engineered MOFs in the delivery of drugs and bioactive enzymes, with a specific focus on their loading mechanisms, such as physical adsorption and ligand-mediated conjugation. 3.1. Drug delivery Recently, the rapid development of MOF-based drug delivery systems has demonstrated various universal delivery modes, including direct drug delivery, [7, 102] drug conjugation, [103] and drugs functioning as linkers. [104, 105] These systems can be synthesized using one-step or two-step methods. [106] However, encapsulated drugs often face stability issues, with small amounts of cargo potentially lost during cleaning, circulation, or transport, leading to suboptimal drug loading. Although drugs conjugated to metal nodes or ligands can be immobilized, significant coordination modifications can alter the crystallographic characteristics of MOFs, compromising the stability of the delivery system. Fortunately, Defect-MOFs facilitate high-capacity drug loading by creating specialized coordination vacancies or expanded pores, while simultaneously enabling precisely controlled, on-demand release. Li et al, [28] prepared the defect- MOFs (UiO-66-NH 2 ) by reducing ligands and adding modulators, compared with defect-free UiO-66-NH 2 , the loading capacity increased more than twofold. Kazemi and co-workers, [29] reported the Defect-MOFs (MOF-808 a ), enables the drug encapsulation, while facilitating intelligent pH-responsive release within acidic environments. The co-existence of hybrid linkers as a unique strategy of defect engineered, open up the multivariate functionality and properties in Defect-MOFs, the monomeric ligands (modulators) compete with the linkers for metal clusters thus leading to fantastic crystallinity and porosity, which can enhance the encapsulation of drug. [107] According to Morris et al, [27] as illustrated in Fig. 11(A), DCA acts as a co-modulator in the synthesis of drug-modulated MOFs and their post-synthetic drug loading (as exemplified by the de novo and Post-synthesis processing introduced in Section 2), enabling the encapsulation of multiple drugs. In Fig. 11(B), the three-drug formulation, α-CHC/AL/DCA@UiO-66 increased the IC50 on MCF-7 cells, approximately 1.5 times the dose of the free drug AL. Many researches have demonstrated the immense potential of defect-MOFs for multi-drug encapsulation and controlled release , [108] Lazaro et al, [109] constructed the Defect-MOFs (DCA@Zr-fum) with small size Fig. 11(C) , by loading DCA into Zr-fum through ligand coordination competition, and subsequently investigated the drug delivery performance of these Defect-MOFs. As shown in Fig. 11(D), cells demonstrated strong uptake of the small-sized Defect-MOFs, enabling selective tumor cell treatment while exhibiting good biocompatibility. The defects in Zr-MOFs, created through competition between drug molecules and ligands, enable multidrug loading and provide a universal platform for multimodal chemotherapy. Similarly, Professor Ross S. Forgan, [110] synthesized multi-drug loaded Defect-MOFs using DCA as co-modulator in Fig. 11(E) . This simultaneous covalent attachment of drugs prevents burst release and enables controlled, sustained delivery. Additionally, the system demonstrated significant cell selectivity, showing compatibility with MCF-7 and HEK293 cells without triggering an immune response, while exhibiting strong cytotoxicity toward HeLa cells in Fig. 11(F) . Fig. 11. (A) DCA acts as a co-modulator for Defect-MOFs (B) The IC50 of defect-MOFs loaded with drugs. [27] Copyright © 2020 Wiley-VCH Verlag GmbH & Co. (C) small size Defect-MOFs (DCA@Zr-fum). (D) Selective treatment and biocompatibility of DCA@Zr-fum. [108] Copyright © 2018 American Chemical Society. (E) Multi-drug loaded with DCA as a co-modulator in Defect-MOFs. (F) Cell selectivity and without triggering an immune response. [109] Copyright © 2018 American Chemical Society. Previously, we discussed the excellent performance of Defect-MOFs in drug delivery. For the complex tumor microenvironment, the therapeutic efficiency of drugs should also be concerned. [36] For example, the tumor microenvironment contains an excess of the reducing substance glutathione (GSH), which has a potential impact on most drugs that generate ROS. To solve this problem, Wang et al, [35] designed a ligand missed Defect-MOFs (Prussian blue analogue, PBA) for loading ATS and Ce6 as a therapeutic strategy, as shown in Fig. 12(A) , (1) Mn 2+ catalyzed bicarbonate-activated H 2 O 2 , which was subsequently converted to ROS by ATS. (2) Ce6-mediated photodynamic therapy. (3) Ligand [CoIII(CN) 6 ] scavenges the antioxidant GSH. Fig. 12(B) illustrates the cytotoxic effects of ATS on 4T1 cells in the presence of various ions, with results demonstrating that the synergistic interaction between ATS and Mn²⁺ exhibits the strongest killing efficacy against 4T1 cells. MCA represents the loading of ATS into Defect-MOFs via one-step synthesis. Similarly, MCC and MCCA are denote the simultaneous loading of Ce6 or Ce6 and ATS into Defect-MOFs, resulting in Fig. 12(C) , the highest tumor cytotoxicity of MCA can be observed, In Fig. 12(D) , demonstrates the tumor inhibition effects of Ce6, MCC, and MCCA, under 660nm LED light, MCCA achieving a killing efficiency as high as 87.1%. Undoubtedly, this work demonstrates the Defect-MOFs can be used as benign carriers for drugs and other small molecules, providing a new direction for the construction of diagnostic and therapeutic compliant nanomedicine. Peng et al [111] immobilized a ferroptosis drug (hygroscopic acetic acid, PAB) in Defect-MOFs, which not only enhanced delivery stability but also downregulated GSH, as shown in Fig. 12(E) . Briefly, Fe 3+ first self-assembled with the carboxyl group of PAB through coordination to form Defect-MOFs precursors, organic ligands were then added to further coordinate with Fe 3+ . This dual-channel GSH eliminator accumulated large amounts of H 2 O 2 for the Fenton-like reaction, which ultimately enhanced cell membrane lipid peroxidation (LPO), and DOX loading for multi-mode therapeutic. Thermogravimetric analysis (TGA) provides first-hand information to assess the existence of defects and the extent of PAB encapsulation, as shown in Fig. 12(F), the upregulation ability of ROS and the scavenging ability of GSH were well demonstrated by Fig. 12(G,H). These promising “ferroptosis + chemotherapy” candidate has shown excellent stability for tumor treatment, Meanwhile, it provides new design schemes and guidance for Defect-MOFs in improving therapeutic efficacy and alleviating drug resistance. In conclusion, the Defect-MOFs drug delivery system offers high stability and efficient drug delivery capacity, compensating for the limited cellular uptake of endogenous drugs and serving as a versatile carrier for tumor therapy. Its customizable structure supports individualized drug development, precise dosing, and efficacy monitoring. Moving forward, researchers can further optimize drug release by incorporating pre-drug constructs with varied coordination strengths to standardize release sequences and doses, enabling precise, on-demand delivery. Fig. 12. (A) MCCA for synergistic therapy. (B) The cytotoxic effects of ATS on 4T1 cells in the presence of various ions. (C) The toxicity of MCA to tumor cells. (D) The tumor inhibition effects of MCCA. [35] Copyright © 2021 Wiley-VCH GmbH. (E) Multi-drug delivery nanoplatform for ferroptosis-based cancer therapy. (F) Thermogravimetric analysis. (G) ROS assay kit analysis of MCF-7/ADR cells. (H) Intracellular GSH levels in MCF-7/ADR cells; n = 3. [111] Copyright © 2021 Elsevier B.V. on behalf of KeAi Communications Co. Ltd. 3.2. Enzyme immobilization and delivery Enzymes have been extensively investigated as potent biotherapeutic agents owing to their exceptional catalytic efficiency and high substrate specificity. [112] However, the inherent structural simplicity and instability of enzymes such as their susceptibility to oxidation and decomposition in the biological microenvironment limit their broader application in biomedicine. Fortunately, MOFs have shown great promise in extreme environments, as porous network structures provide selective mass transfer platforms for substrates and enhance catalysis. [113] A large number of enzyme-MOFs platforms have been synthesized by in situ encapsulation, [114, 115] pore entrapment, [116, 117] and surface immobilization. [118] However, these conventional structures may not be ideal for enzyme loading and delivery, and could even hinder substrate diffusion, making it difficult for enzyme molecules encapsulated in the crystal framework to interact efficiently with substrates. [119, 120] Therefore, Defect-MOFs have emerged as pivotal materials for achieving high-capacity enzyme loading and significantly enhancing catalytic performance. [121-123] The distribution of pore sizes enhances enzyme immobilization by reducing mass transfer resistance and overcoming diffusion limitations. The non-uniform structure of Defect-MOFs facilitates substrate transport within a stable framework, allowing for the co-loading and release of enzymes. [124] For instance, Feng et al, [30] successfully encapsulated glucose oxidase (GOx) into ZIF-8 with defect engineered by replacing ligands, and achieving intelligent delivery of insulin. They found that the amount of 1-methylimidazole in the amount of 1-methylimidazole affects the relative enzymatic activity of GOx@d-ZIF-8. The loading efficiency of GOx was approximately 3.1%, as measured by the Bradford method, which was higher than the 2.8% achieved with GOx@ZIF-8, indicating a significant enhancement in enzyme loading due to the defective structure. Briefly, substitutions between 1-methylimidazole and 2-methylimidazole interfered with the structural integrity of ZIF-8, leading to framework rearrangements and mesopores, which were attributed to coordination interactions between the altered metal atom and the new organic ligand, as shown in Fig. 13(A,B) . The defects enhanced the loading capacity of ZIF-8, increasing enzymatic activity and the number of active sites, meanwhile the faster dissociation of the ZIF-8 framework enabled precise drug release. High glucose concentrations promoted effective insulin release, while insulin release was minimal at low glucose concentrations, as depicted in Fig. 13(C,D) . This work demonstrates how defect-engineered enzyme-immobilized materials can enhance enzyme activity and enable intelligent drug delivery systems responsive to specific chemical signals, paving the way for precision therapy. In another research, Hu et al, [125] proposed a novel strategy for constructing defect structures in MOF-enzyme systems using microfluidic techniques, reporting a ternary mixing scheme that significantly enhances substrate affinity and enzyme activity. This technique introduces new hydrodynamic properties to the complexes by continuously varying precursor concentrations during small-scale fluid processing, creating concentration gradients that perturb complex formation and generate defects. They found that proteins initially adsorb organic ligands, which then induce bionic mineralization to form Defect-MOFs structures. The continuously varied reactant ratios lead to defects in the MOF crystal structure, eliminating the template dependence of conventional methods and potentially generalizable to biological macromolecules. Defect engineering makes MOFs more suitable as host materials for enzymes, optimizing the activity, recoverability, and stability of the loaded enzymes. As observed, enzyme-defect-engineered MOF complexes with different hybrid schemes exhibit varying activities, likely due to the distinct immobilization sites of the enzymes. Future research could focus on modulating the local properties of defect sites to expand the range of loadable enzymes and develop specific immobilization strategies. Additionally, studying the spatial distribution of enzymes within defect-engineered MOFs will enhance understanding of catalytic behavior and mechanisms, leading to improved methods for enhancing enzyme catalytic performance. Fig. 13. (A) pH-responsive drug release of GOx@d-ZIF-8. (B) Pore size distributions for GOx@ZIF-8 and GOx@d-ZIF-8. (C) FITC-labelled insulin releasing from Insulin&GOx@ZIF-8 in glucose solution. (D) The change of pH corresponding to the process of FITC-labelled insulin releasing from Insulin&GOx@ZIF-8. [30] Copyright © 2022 Elsevier B.V. 4. Defect-engineered MOFs for enhanced tumor Theranostics Various drugs including inorganic nano-drugs, organic large/small molecule drugs, and functional natural drugs have shown initial satisfactory therapeutic effects, and providing alternative strategies for diverse cancer treatments. [126] As discussed in the previous section, various drugs can serve as ligands for Defect-MOFs, which helps improve drug biocompatibility and enhances therapeutic effects. Nowadays, research efforts increasingly focus on modifying and optimizing the central atoms and ligands in Defect-MOFs to enhance their effectiveness for theranostic applications. [127, 128] More importantly, the unsaturated metal centers generated by defects significantly modulate the global electronic structure of the framework, thereby conferring exceptional catalytic kinetic properties. This defect based catalytic intensification can synergize with radiotherapy, dynamic therapies, and photothermal therapy to trigger the robust generation of reactive oxygen species within the tumor microenvironment. [129-131] Consequently, these defect-induced active sites facilitate the effective integration of various therapeutic agents and functional cargoes, establishing a robust foundation for multimodal synergistic cancer treatment. [132] 4.1. Defect-engineered MOFs for enhanced tumor marker detection and diagnosis Early diagnosis based on tumor markers plays an important role in diagnosis and treatment, also “early detection and treatment” can significantly improve survival rates. [133] However, conventional imaging methods often face limitations in spatial resolution, making the detection of cancer metabolites more suitable for achieving non-invasive and real-time monitoring goals. [134] Yang et al, [135] reported the development of signal-enhancing Defect-MOFs Fig. 14(A) . These Defect-MOFs served as matrix materials for mass spectrometry-based detection of small metabolic markers, achieving up to a 10,000-fold signal enhancement resulting in diagnosis of three major cancers (liver/lung/kidney cancer) with area-under-the-curve of 0.908–0.964 and accuracy of 83.2%–90.6%. In the age and sex characteristics of 305 individuals Fig. 14(B) Fe-MOF-UL showed specific selectivity in three groups (including liver, lung, and kidney cancer) of cancer patients Fig. 14(C) . According to Fig. 14(D) further evaluation with 305 serum samples from cancer patients and healthy controls revealed that Fe-MOF-UL, provided a substantial detection advantage, showing more signals and total ion counts. In short, this metabolic marker detection platform demonstrated several advantages: a low sample requirement (only 0.1 µl of serum per person), rapid processing time (<1 min per person), and high analytical throughput (~110-250 metabolic signals). The diagnostic accuracies for liver, lung, and kidney cancers were 89.8%, 83.2%, and 90.6%, respectively. This work demonstrates the effectiveness of using Defect-MOFs as substrates for biological detection markers, achieving ultra-high sensitivity and providing substantial support for early tumor screening and detection. More recently in 2026, Wu et al, [136] report a defect-NOFs for the highly sensitive sensing of 5-hydroxyindole-3-acetic acid (5-HIAA), a key carcinoid biomarker. Fig.14(E) . In this work, DM-UiO-66 demonstrates a remarkable “turn-on” fluorescence response to 5-HIAA, achieving an 18-fold enhancement in intensity, which is far superior to the merely 1.2-fold increase observed for pristine UiO-66. As shown in Fig. 14(F) , the consistent trend of the intensity ratio I/I 0 in both aqueous and artificial urine environments demonstrates the robust stability of DM-UiO-66 against complex matrices. Furthermore, a BP neural network was employed to correlate the predicted 5-HIAA concentrations with actual values. The linear fit in Fig. 14(G) yields a correlation coefficient (R 2 ) of 0.996, highlighting the high reliability and intelligence of the sensing system. Fig. 14. (A) Defect-MOFs (Fe-MOF-UL) for detection and diagnosis. (B) Age and gender characteristics of cancer patients. (C) Representative mass spectra of cancer patients. (D) The signal numbers and averaged TIC extracted from the liver/lung/kidney group. Copyright © 2022 Wiley-VCH GmbH. (E) Defect-MOFs (DM-UiO-66) for detection and diagnosis. (F) The contrast of I/I 0 of DM-UiO-66 under different 5-HIAA contents between the aqueous solution and urine. (G) Predictions of 5-HIAA concentration based on linear fitting. [136] Copyright © 2025 Elsevier B.V. 4.2. Defect-engineered MOFs for enhanced radiotherapy Radiation therapy (RT), which relies on the activation of specific radiotracers and external radiation. 125 I 2 implantation, is a type of brachytherapy with highly effective technique for comprehensive malignant tumor treatment. By continuously irradiating tumor tissue, 125 I 2 emits gamma rays during decay that emits gamma rays that destroy tumor cells and nearby depleted cells, while also inhibiting tumor cell proliferation. [137] However, uncontrollable changes in tumor volume often require an increase in the number of puncture injections, may lead to intra-organ spread of tumor cells and tissue damage. To maximize the therapeutic benefits of radiotherapy while decreasing the frequency of puncture administrations and reducing the side effects of treatments. Tian et al, [138] developed a novel synthesis of defect-engineered MOFs (ZIF-8+) by doping with iodinated 2,3-dimethyl-1H-imidazole (Dmim) as an auxiliary ligand. This approach enhanced the I 2 adsorption capacity significantly, as the intrinsic iodide component (I⁻) of the framework can react with I 2 to form I 3 - or other polyiodide anions, this Defect-MOFs exhibit significant antitumor activity. Meanwhile, RT relies on generating a large amount of ROS within the tumor to achieve therapeutic effects, [139] but the hypoxic environment in tumor limits the efficacy of radiotherapy. [140] To solve this problem, Lin et al, [140] first introduced a novel therapeutic strategy that synergizes low-dose X-ray radiodynamic therapy (RT-RDT) with checkpoint blockade immunotherapy using Defect-MOFs (DBP-Hf nMOF) to enhance radiotherapy and in situ immunity. More recently in 2026, Lin and co-wokers, [141] Utilizing a spatial confinement strategy, a multifunctional platform was developed that integrates high-Z element-mediated radiotherapy (RT) enhancement with catalytic redox modulation and sustained chemotherapeutic delivery. As illustrated in Fig. 15(A) , platinum nanoclusters (PtNCs) were encapsulated within the Hf-Ir-DBB MOF via a photoreduction method. Upon X-ray irradiation, this nanoplatform significantly bolsters the generation of ROS, effectively overcoming the intrinsic constraints of the tumor microenvironment (TME) to amplify RT efficacy. As shown in Fig. 15(B) , a robust production of oxygen was observed, which alleviates tumor hypoxia—a critical factor in preventing RT resistance and immune evasion. Synergized by X-ray-triggered chemotherapy, the system achieved a substantial tumor growth inhibition rate of 53.8%. Fig. 15(C) . Furthermore, the platform successfully remodeled the tumor stroma and promoted the infiltration of CD8 + T cells, thereby eliciting potent systemic immune activation. 4.3. Defect-engineered MOFs for enhanced sonodynamic therapy Sonodynamic therapy (SDT) utilizes ultrasound with excellent penetrating properties to stimulate the generation of toxic ROS from acoustic sensitizers, which is particularly suitable for deep tumor treatment. [142] However, conventional acoustic sensitizers are generally limited by the rapid electron-hole recombination and the potential organ toxicity due to difficult degradation [143] . Therefore, developing acoustic sensitizers that efficiently generate ROS and exhibit good biosafety for sonodynamic therapy (SDT) is crucial. Defect-MOFs, with their tunable band gaps, effectively reduce the electron-hole recombination rate, making them an ideal nano-agent for SDT. [144] Lin et al, [39] reported the defect-engineered NH 2 -MIL-125 (MOF-Ti) D-MOF(Ti), which exhibited enhanced photoactivated modulation of ROS. Recently, Liu et al, [50] reported Ti-doped UiO-66 (UTN) synthesized via defect engineering Fig. 15(D) , and revealed the mechanism of defect-driven enhancement in SDT. As shown in Fig. 15(E) the comparison of sonocurrent intensities between UiO-66, UTN exhibits a significantly higher steady-state sonocurrent density. According to Fig. 15(F) , the tumor inhibition rate of the UTN+US group reached 86.07%. These results demonstrate that defect engineering plays a crucial role in breaking the constraints between ligands and metal atoms, enhancing electron transfer, and reshaping the electronic environment to boost electron activity near the Fermi level. This study provides new insights and theoretical support for utilizing defect-engineered MOFs in enhanced sonodynamic therapy. 4.4. Defect-engineered MOFs for enhanced immunotherapy Immunotherapy can treat tumors and provide long-term prevention by regulating immune cell function and activating T cells for specific recognition. [145, 146] Immunogenic cell death (ICD) has emerged as an effective method to activate the immune system. Tumor cells treated with drugs release a series of damage-associated molecular patterns (DAMPs) that act as signals to wake up the immune system, thereby enhancing the effectiveness of immunotherapy. [147] However, exposed phosphatidylserine (PS) often hinders DAMP expression thus resisting antitumor immunity. [148] Therefore, to amplify the ICD effect and inhibit PS interference, Dai et al, [149] reported to inhibit the PS activator transmembrane protein and replace Zn 2+ in MOF-5 with Gd 3+ that can compete with Ca 2+ for enzyme binding sites on the cell membrane. As shown in Fig. 15(G) , the bimetals in the synthesized Defect-MOFs (Gd-MOF-5) inhibited phosphatidylserine (PS) externalization and induced mitochondrial dysfunction, thereby enhancing the effectiveness of immunotherapy. The 4T1 breast cancer cells treated with Gd-MOF-5 showed significantly lower cell viability than those treated with MOF-5 after 24 hours, as shown in Fig. 15(H) . Annexin V was used as an indicator to assess the inhibition of phosphatidylserine (PS) exposure by Gd-MOF-5. PS exposure occurred as expected in cells treated with MOF-5 or chemotherapeutic drugs, whereas PS exposure was significantly reduced in the Gd-MOF-5 group. Fig. 15(I) illustrates that Ca 2+ and PS exposure were significantly increased in cells treated with MOF-5, while Gd-MOF-5 effectively inhibited PS exposure. This suggests that Gd 3+ may reduce activated PS exposure by competing with Ca 2+ for binding to TMEM 16F. Therefore, Defect-MOFs, through their defect sites, can protect substances and enhance immunotherapy and the multi-metal coexistence in MOFs may open up multiple pathways for protein inhibition and activation. Fig. 15. (A) Defect-MOFs for radiotherapy. (B) ROS generation at X-ray irradiation. (C) Tumor growth curves of CT26-bearing mice after different treatments [141] Copyright © 2026, American Chemical Society. (D) Defect-MOFs for sonodynamic therapy. (E) The comparison of sonocurrent intensities between UiO-66 and UTN. (F) Tumor inhibition rate of the UTN+US. [50] Copyright © 2025 Wiley-VCH GmbH. (G) Defect-MOFs for immunotherapy. (H) 4T1 cells treated with MOF-5 and Gd-MOF-5 nanoparticles for 24 h. (I) Quantitative analysis of PS exposure level using Annexin V staining. [149] Copyright © 2021 Elsevier Ltd. All rights reserved. 4.5. Defect-engineered MOFs for enhanced Photo-/Chemo- dynamic therapy Photodynamic therapy (PDT) is a promising therapeutic strategy due to its non-invasive nature and the ability to achieve spatiotemporal control via light exposure. In this process, the photosensitizer induces the conversion of O 2 in the tumor microenvironment (TME) to cytotoxic singlet oxygen ( 1 O 2 ), leading to damage to tumor tissue under light exposure. [150] However, the hypoxic conditions in the TME and the instability of photosensitive materials under light exposure limit the clinical effectiveness of PDT. [151] Fortunately, Defect-MOFs, by introducing missing-linkers or missing-clusters, create abundant coordinatively unsaturated metal sites and hierarchical porous structures within the framework, synergistically enhancing PDT. For instance, Liu et al, [152] employed Defect-MOFs (based on MOF-199) to load photosensitizers, constructing a composite nanoplatform that enables GSH-responsive release of the photosensitizer in the tumor microenvironment, while Cu 2+ effectively deplete GSH to amplify PDT efficacy ( Fig.16(A) ). Considering the sustained PDT performance and biodegradability of these platforms, Qu et al, [153] developed ultrasmall porphyrinic Defect-MOFs quantum dot (QDs) with abundant defect sites via a nanoscale “top-down” synthesis strategy. Under identical light irradiation, these Defect-MOFs QDs generated twice the reactive oxygen species (ROS) compared to defect-free MOFs, overcoming the limited diffusion distance of ROS while maintaining excellent biodegradability and metabolic clearance in vivo ( Fig.16(B) ). In recent years, the emergence of chemodynamic therapy (CDT) has provided new inspiration for augmenting PDT. [154] Recently, Jiao et al, [132] reported a Defect-MOFs nanoplatform (Fe-UiO@HA) for synergistic PDT/CDT. Defect engineering significantly improved the separation and migration efficiency of photogenerated electron-hole pairs, thereby enhancing PDT. Moreover, the GSH oxidase-like activity and Fenton-like reaction of Fe-UiO@HA further boosted ROS production, substantially amplifying the therapeutic outcome( Fig.16(C) ). Furthermore, Rigau et al, [155] utilized defect engineering to regulate the hierarchical porous structure of HP-UiO-66, enabling efficient hemoglobin loading while improving biocompatibility( Fig.16(D) ). This work introduces a novel “inside-out” strategy for constructing and innovating Defect-MOFs, offering fresh insights for hypoxia alleviation and tumor microenvironment remodeling in cancer therapy. Fig. 16. (A) Defect-MOFs(MOFs-199) for PDT. [152] Copyright © 2019 American Chemical Society. (B) Defect-MOFs QDs for enhanced PDT. [153] Copyright © 2019 American Chemical Society. (C)Defect-MOFs for PDT and CDT combined Therapy. [132] Copyright © 2026 American Chemical Society . (D) Hierarchical Porous of Defect-MOFs for biomacromolecule. [155] Copyright © 2025 American Chemical Society . 4.6. Defect-engineered MOFs for enhanced photothermal therapy Photothermal therapy PTT relies on convert light energy into heat under near-infrared light (NIR) irradiation, leading to localized heating at the tumor site to inhibit tumor growth. [156, 157] Although defect-free MOFs have been extensively employed in synergistic photothermal therapy, the local inflammation and oxidative stress induced by photothermal effects often compromise therapeutic outcomes. [158] In contrast, Defect-MOFs, with unsaturated metal sites or oxygen vacancies and superior photothermal conversion efficiency, have widely application in photothermal enhanced catalysis. [159] In recent years, researchers adopted Defect-MOFs derived composites, leveraging pyrolysis engineering to generate additional defects, which facilitate catalytic alleviation of oxidative stress, thereby substantially improving the efficacy and biocompatibility of mild-temperature PTT. As shown in Fig. 17(A). Weng et al, [160] synthesized a series of PTAs, denoted as Cu@CPP-t, composed of copper nanoparticles supported by defective porous carbon polyhedra. They observed that the organic ligands were converted into porous graphitic carbon materials with defects, while the coordinated metal ions were reduced to nanoparticles or metal oxides. According to Fig. 17(B) , the Cu nanoparticles remained uniformly dispersed on the carbon support. As authors reported that the increase in defects resulted from stronger interactions between the abundant supported Cu and the carbon, causing significant structural distortion. Moreover, the growth of Cu nanoparticle size with higher annealing temperatures intensified these interactions, leading to an increase in defects at the interface. As shown in Fig. 17(C,D). Under 808 nm NIR irradiation, the material demonstrated favorable photothermal conversion efficiency, with Cu@CPP-t exhibiting significantly better photothermal conversion than Cu-BTC. After intravenous administration of Cu@CPP-800 (1 mg kg -1 ) to tumor-bearing mice, the temperature at the tumor site increased from 30.1°C to 58.3°C within 3 minutes Fig. 17(E) , demonstrating the remarkable photothermal response of the material. This study highlights that Defect-MOFs can serve as novel photothermal enhancers, further improving photothermal conversion efficiency and providing a new option for photothermal therapy. Recently, Xu et al, [161] reported a Defect-MOFs derived composite for synergistic photothermal and immunotherapy. As illustrated in Fig. 17(F) , this platform not only achieves highly efficient PTT but also plays an important role in tumor stroma remodeling. The photothermal conversion performance of the system is detailed in Fig. 17(G) . Notably, the defects introduced via the pyrolysis process effectively stabilize the electron-hole pairs within the composite (Fig. 17H,I) , significantly enhancing charge separation. This defect-mediated electronic modulation further facilitates the substantial depletion of GSH within the tumor microenvironment, and tumor stroma remodeling. While research on Defect-MOFs derived composites for synergistic PTT is flourishing, challenges such as pyrolysis-induced aggregation and uncontrollable defect distribution remain significant. Consequently, there is a need for focus on the in situ synthesis of Defect-MOFs loaded with photothermal agents. Leveraging their abundant active sites to amplify therapeutic efficacy represents a vital direction for future investigation. Fig. 17. (A) Cu@CPP-t for PTT. (B) High-resolution TEM image of Cu@CPP-800 (C) Photothermal heating curves for Cu@CPP-800 dispersions. (D) Infrared thermal images of Cu@CPP-800 and Cu-BTC in aqueous. (E) NIR in vivo photothermal imaging. [160] Copyright © 2019 WILEY-VCH Verlag GmbH & Co. (F) Defect-MOFs derived composite for PTT. (G) Photothermal conversion performance of MCT x . (H) Mechanism of defect enhanced catalytic. (I) GSH degradation of MCT x . [161] Copyright © 2024 American Chemical Society. 4.7. Defect-engineered MOFs for all-in-one therapeutic In recent years, the concept of theranostics has been proposed to achieve early diagnosis and precision therapy for tumors. As discussed in previous sections, MOF-based theranostic nanoplatforms have made significant strides in multimodal imaging and multifunctional therapy. [162, 163] However, while the near-perfect crystalline lattice of traditional MOFs ensures structural stability, it also results in uniform pore size distributions and limited accessible active sites, posing challenges for the encapsulation of guest molecules with diverse dimensions. In contrast, Defect-MOFs engineered through the intentional introduction of ligand or nodal vacancies during the growth process transcend the constraints of long-range periodic order. This structural confers highly tunable physicochemical properties, providing expanded possibilities for the loading and conjugation of functional guest molecules. From an application perspective, Yang et al, [164] constructed a Defect-MOFs (Cypate@MIL-53/PEG-Tf) by leveraging the interaction between the carboxyl groups of cypate molecules and Fe 3+ , achieving multimodal imaging (NIRF/PAI/MRI)-guided targeted PTT/PDT( Fig.18(A) ). Tian et al, [165] employed a dual-ligand self-assembly defect-engineering strategy to co-integrate cypate and H 2 TCPP into a Zr-MOF (PC20-MOF-FA). This approach prevented accidental molecular leakage and achieved synergistic PDT/PTT through the combined effects of porphyrin and cypate, resulting in a tumor inhibition rate of ~97.15% alongside integrated fluorescence/photoacoustic/thermal multimodal imaging( Fig.18(B) ). It is well-established that Defect-MOFs also serve as highly efficient catalytic materials, [166] a characteristic that warrants significant attention when designing theranostic nanoplatforms. Furthermore, the biocompatibility of multi-component composites remains a critical consideration, [167] In the context of clinical translation, the ability to achieve a ”1+1>2” therapeutic effect through simplified material compositions is a fundamental prerequisite for the future application of Defect-MOFs. Simultaneously, there is increasing anticipation for a new paradigm of once treatment and durable immunity in therapy. Recent pioneering research has provided fresh insights into this field. Tu et al, [168] reported a piezoelectric Defect-MOF (DHME) where the defective structure facilitates massive ROS generation under ultrasound activation. As a robust carrier for the demethylation agent epigallocatechin gallate (EGCG), this system significantly promotes cell death and immune activation through the synergy of enhanced oxidative stress and epigenetic reprogramming. More recently, the strategy of synergistic therapy via innate immune activation has demonstrated even greater clinical feasibility( Fig.18(C) ). Zhao et al, [169] developed a sophisticated Defect-MOF (Ir@D-Cu-HITP-MMP) through defect engineering to disrupt the electronic symmetry of single-atom catalysis. By constructing asymmetric electronic distribution centers, this design not only endows the material with exceptional catalytic activity to induce cuproptosis and mild photothermal effects but also ingeniously incorporates MerTK-mediated innate immune-checkpoint blockade( Fig.18(D) ). This represents a novel “all-in-one” therapeutic mode, where the optimization of the electronic environment via defect regulation provides a transformative paradigm for the further development of Defect-MOF-based nanotherapeutic platforms. Fig.18. (A)Defect-MOFs(Cypate@MIL-53/PEG-Tf) for imaging and guided phototherapy. [164] Copyright © 2019 American Chemical Society. (B) Defect-MOFs(PC20-MOF-FA) for targeting multimodal cancer phototheranostics. [165] Copyright © 2021 Royal Society of Chemistry (C) Defect-MOF (DHME) for pyroptosis and immunotherapy. [168] Copyright © 2026 Elsevier B.V. (D) Defective single-site nanozymes for all in one therapeutic. [169] Copyright © 2026 American Chemical Society. Table 1. Synthesis of Defect-MOFs for enhanced tumor Theranostics. ZIF-8 Miss linker Post-synthetic CDT [114] ZIF-8 Ligand Substitution De novo Enzyme encapsulation [30] UIO-66 Ligand Substitution De novo Drug delivery [107] Zr-fum Ligand Substitution De novo Drug delivery. [109] UiO-66 Ligand Substitution De novo Drug delivery [110] Prussian blue analogues Missing Ligand De novo Drug delivery [35] MIL-53 Ligand Substitution De novo Drug delivery [111] ZIF-8 Ligand Substitution De novo Drug delivery [138] TCPP–Hf Metal Cluster Substitution Post-synthetic RT [170] MIL-125 Missing Metal Cluster Post-synthetic SDT [39] MOF-5 Metal Cluster Substitution De novo Immunotherapy [149] Prussian blue analogues Metal Cluster Substitution De novo CDT [171] UIO-66 Metal Cluster Substitution (Doping) Post-synthetic PDT [172] Zr(IV)-based porphyrinic MOFs Ligand Substitution De novo PDT [173] Cu-BTC Missing Ligand Post-synthetic PDT [174] MIL-53 Missing Metal Cluster Post-synthetic Diagnosis [135] PCN-224 Ligand Substitution De novo Imaging guided therapy [165] MIL-53 Ligand Substitution Post-synthetic MRI guided therapy [164] Hf-UiO-66 Ligand Substitution De novo All in one. [175] Cu-TPH Metal Cluster Substitution Post-synthetic CDT [167] UiO-66 Metal Cluster Substitution De novo Diagnosis and treatment [176] Fe/Mn-dhtp Metal Cluster Substitution De novo Diagnosis and treatment [177] ZIF-8 Metal Cluster Substitution De novo CDT [178] ZIF-8 Metal Cluster Substitution De novo CDT [179] 5. Conclusion and outlook In this review, we critically assess the advantages and limitations of defect engineering in designing MOFs, systematically classifying their synthesis methods and exploring their biomedical applications, particularly in enhanced drug delivery and efficient theranostics. Recent progress in targeted design, structural tunability, and practical utility has enabled researchers to exploit the unique pore architectures, chemical stability, and abundant active sites of Defect-MOFs, developing versatile platforms for drug delivery and combination therapies. Despite these advances, the field remains in its early stages, and addressing persistent challenges is essential for future development. In drug delivery, Defect-MOFs, with their high porosity and versatile linkage sites, support drug transport strategies such as drug loading, electrostatic adsorption, and functional group linkage. These properties make them ideal for delivering chemically unstable or hydrophobic drugs. However, challenges like premature drug release in complex biological environments can be mitigated by tumor microenvironment-responsive designs (e.g., acidity or redox triggers), enabling controlled release and adaptive motion. Their unique structures and large surface area improve energy absorption and catalytic reactions, enhancing mobility within tumors. Functionalization of active sites allows targeting specific molecules or proteins, further improving drug absorption. Addressing challenges such as transmembrane transport and drug absorption is crucial for targeted drug delivery. Defect-MOFs, with abundant active sites and exposed linkers, can be functionalized to target specific molecules or proteins, improving drug absorption. The use of natural herbal compounds in self-assembly and functionalized designs has also gained attention, offering pathways for biocompatible drug delivery systems. Integrating natural product components into Defect-MOF linkers could yield materials with inherent bioactive properties. Advancing drug delivery applications will require interdisciplinary collaboration and comprehensive in vivo and clinical trials to assess biocompatibility, pharmacology, and toxicity, paving the way for biomedical translation. In tumor therapy, Defect-MOFs, with abundant reactive sites, facilitate efficient reactions in the tumor microenvironment, such as enhancing H 2 O 2 decomposition to boost reactive oxygen species (ROS) production in chemodynamic therapy. Their exceptional performance in tumor treatments relies on improved physicochemical properties. Future research could refine defect structures via ion doping, substitution, or ligand exchange to adjust band gaps, energy levels, and responsiveness to stimuli like light or magnetism. These strategies enhance electron-hole separation and reactive species generation. Additionally, leveraging reducing agents like glutathione (GSH) can amplify catalytic reactions for multimodal therapies. Defect engineering, including the introduction of specific metal ions, improves photothermal conversion efficiency. Exploring Defect-MOFs effects on mitochondrial metabolism and designing ligands for mitochondrial targeting could advance precision tumor treatments. Currently, AI, particularly machine learning, can predict optimal defect types in Defect-MOFs (e.g., missing linkers, and metal vacancies), optimize synthesis conditions, and assist in analyzing defect distributions and their impact on MOF functionality. By integrating the tunable properties of Defect-MOFs with AI predictive and analytical capabilities, researchers can develop innovative platforms for targeted drug delivery, real-time diagnostics, and combination therapies, reducing development time and costs while accelerating translational and clinical applications. [180, 181] Despite the promise of integrating AI with Defect-MOFs for future intelligent theranostic, several challenges persist. For example, AI models rely on high-quality, large-scale datasets, yet current structure-property data for Defect-MOFs, particularly experimental data for biomedical applications, remain limited, constraining the accuracy and generalizability of AI predictions. Researchers can collaborate to establish a standardized Defect-MOFs database, integrating structural parameters, performance metrics, and biomedical experimental outcomes. Additionally, data augmentation techniques, such as generating virtual datasets from existing Defect-MOFs data, can mitigate the scarcity of experimental data. Leveraging the programmable and unique physicochemical properties of Defect-MOFs, and combined with synergistic advancements in AI, we are confident that these innovations will significantly accelerate the translation from laboratory to clinical applications, particularly in personalized cancer therapies, real-time disease monitoring, and the development of multifunctional theranostic platforms. Acknowledgement This work was funded by the National Natural Science Foundation of China (No. 52372264, No. 52473109, No. 22371162), the Natural Science Foundation of Heilongjiang Province (No. LH2023B002), the Fundamental Research Funds for the Central Universities (No. 2572023CT11-05), the Guangdong Innovative and Entrepreneurial Research Team Program (2023ZT10C040), Guangdong Basic and Applied Basic Research Fund (2024A1515010713). Dedication Dedicated to the 2025 Nobel Prize in Chemistry laureates and researchers in the field. References 1. Yaghi, O. M.; Li, H. Hydrothermal Synthesis of a Metal-Organic Framework Containing Large Rectangular Channels. J. Am. Chem. Soc. 1995 , 117 (41), 10401-10402. DOI: 10.1021/ja00146a033. 2. Cai, G.; Yan, P.; Zhang, L.; Zhou, H.; Jiang, H. Metal–Organic Framework-Based Hierarchically Porous Materials: Synthesis and Applications. Chem. Rev. 2021 , 121 , 12278-12326. 3. Wei, Y.; Zhang, M.; Zou, R.; Xu, Q. 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Rao, L.; Yuan, Y.; Shen, X.; Yu, G.; Chen, X. Designing Nanotheranostics with Machine Learning. Nat. Nanotechnol. 2024 , 19 , 1769-1781. (The following will be filled in by the editorial staff) Manuscript received: XXXX, 2024 Manuscript revised: XXXX, 2024 Manuscript accepted: XXXX, 2024 Version of record online: XXXX, 2024 Information & Authors Information Version history V1 Version 1 13 March 2026 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords biomedicine defect engineering defect-mofs modification mofs Authors Affiliations Xiangkai Qiao 0000-0003-2877-1678 Northeast Forestry University College of Chemistry and Chemical Engineering and Resource Utilization View all articles by this author Jiale Liu Tsinghua Shenzhen International Graduate School View all articles by this author Yifan Pei Tsinghua Shenzhen International Graduate School View all articles by this author Zhen Zhang Northeast Forestry University College of Chemistry and Chemical Engineering and Resource Utilization View all articles by this author Pengyu Dai 0009-0009-6014-0041 Northeast Forestry University College of Chemistry and Chemical Engineering and Resource Utilization View all articles by this author Xinze Hu Northeast Forestry University College of Chemistry and Chemical Engineering and Resource Utilization View all articles by this author MOHAMED SYAZWAN OSMAN 0000-0003-3502-4769 Universiti Teknologi MARA - Kampus Pulau Pinang View all articles by this author PAUL SOTO RODRIGUEZ 0000-0002-2425-932X Universidad de La Laguna Departamento de Medicina Fisica y Farmacologia View all articles by this author Dongpyo Kim Harbin Institute of Technology Shenzhen View all articles by this author Lei Wang 0000-0002-9522-3623 [email protected] Harbin Institute of Technology School of Chemistry and Chemical Engineering View all articles by this author Chunxia Chen Northeast Forestry University College of Chemistry and Chemical Engineering and Resource Utilization View all articles by this author Ding Dai Northeast Forestry University College of Chemistry and Chemical Engineering and Resource Utilization View all articles by this author Sanyang Han Tsinghua Shenzhen International Graduate School View all articles by this author Tiedong Sun Northeast Forestry University College of Chemistry and Chemical Engineering and Resource Utilization View all articles by this author Metrics & Citations Metrics Article Usage 240 views 160 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Xiangkai Qiao, Jiale Liu, Yifan Pei, et al. 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