Harnessing the Gut-X Axis: Novel Avenues for Oral Nanomedicine

The gut microbiota plays a pivotal role in regulating host physiology and disease through bidirectional communication with distant organs, known as the Gut-X axis. This axis integrates neuroendocrine, immune, and metabolic pathways, thereby linking gut-derived metabolites to extraintestinal systems. All the time, conventional oral nanodrug delivery systems (NDDS) have largely focus on “point-to-point” targeting of specific organs or lesions, emerging evidence underscores the profound influence of gut microbiota on health and disease across multiple systems. Crucially, many orally administered agents achieve therapeutic effects precisely through the Gut-X axis by mediating trans-organ communication. This paradigm shift opens transformative avenues for oral NDDS. Modern NDDS provide unprecedented spatiotemporal control over therapeutic delivery. By leveraging physiological pathways inherent to the Gut-X axis, advanced NDDS can achieve treatment objectives simply by modulating the composition and activity of gut microbiota. These technologies bridge gut-localized actions with systemic outcomes, enabling dual-path strategies for coordinated multi-organ therapy. This review elucidates the principles of the Gut-X axis, summarizes biological barriers to Gut-X axis-targeted therapies, highlights recent breakthroughs in NDDS interventions exploiting this axis, and discusses the challenges and future prospects of NDDS-mediated multi-organ targeting through the Gut-X axis. Harnessing the Gut-X Axis: Novel Avenues for Oral Nanomedicine

The gut microbiota plays a pivotal role in regulating host physiology and disease through bidirectional communication with distant organs, known as the Gut-X axis. This axis integrates neuroendocrine, immune, and metabolic pathways, thereby linking gut-derived metabolites to extraintestinal systems. All the time, conventional oral nanodrug delivery systems (NDDS) have largely focus on “point-to-point” targeting of specific organs or lesions, emerging evidence underscores the profound influence of gut microbiota on health and disease across multiple systems. Crucially, many orally administered agents achieve therapeutic effects precisely through the Gut-X axis by mediating trans-organ communication. This paradigm shift opens transformative avenues for oral NDDS. Modern NDDS provide unprecedented spatiotemporal control over therapeutic delivery. By leveraging physiological pathways inherent to the Gut-X axis, advanced NDDS can achieve treatment objectives simply by modulating the composition and activity of gut microbiota. These technologies bridge gut-localized actions with systemic outcomes, enabling dual-path strategies for coordinated multi-organ therapy. This review elucidates the principles of the Gut-X axis, summarizes biological barriers to Gut-X axis-targeted therapies, highlights recent breakthroughs in NDDS interventions exploiting this axis, and discusses the challenges and future prospects of NDDS-mediated multi-organ targeting through the Gut-X axis.

Gut-X axis; Oral nanodrug delivery systems; Microbiota modulation; Multi-organ targeting 1 Introduction The gut microbiota, a complex ecosystem comprising trillions of microorganisms, has become a focal point in biomedical research and has been confirmed as a crucial regulator of host physiology and disease, earning the gut its designation as the “second brain”. [1–3] Recent groundbreaking studies have revealed that microbiota and their bioactive metabolites profoundly influence host physiology through dynamic interactions with distant organs. This bidirectional communication, termed the “Gut-X axis”, integrates neuroendocrine, immune, and metabolic pathways to connect the gut microbiota with extraintestinal systems, including the brain, liver, joints, and even tumors. [4,5] For instance, gut-derived short-chain fatty acids (SCFAs) modulate neuroinflammation in Alzheimer’s disease (AD) by crossing the blood-brain barrier and activating microglial homeostasis, while secondary bile acids (e.g., deoxycholic acid) regulate hepatic stellate cell activation, influencing the progression of liver fibrosis. In cancer, microbial metabolites like butyrate enhance antitumor immunity by promoting dendritic cell maturation in tumor-draining lymph nodes. [6–13] This bidirectional regulation highlights the Gut-X axis as a cutting-edge strategy for treating multi-organ diseases. Despite the therapeutic potential of targeting the Gut-X axis, conventional strategies (e.g., probiotic supplementation or metabolite administration) face challenges such as enzymatic degradation, low bioavailability, and insufficient organ-specific delivery. [14,15] Nanodrug delivery systems (NDDS) provide transformative solutions by addressing these limitations synergistically. [16,17] Although significant progress has been made in nanotechnology, conventional oral nanomedicines designed to treat distal diseases still face multiple biological barriers and exhibit limited efficiency in achieving point-to-point targeting via systemic circulation. In contrast, NDDS that leverage the Gut-X axis represent a novel oral delivery strategy that harnesses the body’s inherent inter-organ communication pathways, bypassing the need for direct point-to-point targeting. These systems encapsulate drugs within nanoparticles and modify their surfaces with various ligands to ensure precise delivery to the gut. [18–20] Oral NDDS can protect payloads from degradation in the harsh gastrointestinal environment, thereby enhancing drug delivery efficiency. [21–24] By optimizing physicochemical properties, NDDS improve intestinal retention and interaction with microbial communities. [25,26] Crucially, NDDS leverage the Gut-X axis’s intrinsic pathways, such as microbial metabolite production, immune signaling, and neural circuits, to achieve systemic effects without requiring systemic absorption. [27,28] Current NDDS designs increasingly focus on gut-centric mechanisms, directly reshaping microbial composition or metabolite profiles to indirectly influence remote pathologies. [29–33] Emerging innovations, including surface-functionalized carriers and biomimetic modifications, optimize local gut targeting to amplify systemic therapeutic effects. [34–36] For instance, nanocarriers can be engineered with surface ligands or responsive elements to target gut epithelial cells or microbiota. These designs enhance intestinal retention, protect drugs from gastrointestinal degradation, and trigger precise drug release in response to local pH, enzymes, or microbial metabolites. [37,38] Compared to traditional oral drug delivery, NDDS-mediated strategies through the Gut-X axis offer distinct advantages. By leveraging the gut’s inherent communication pathways, NDDS minimize systemic exposure and off-target effects. [39,40] This paradigm shifts NDDS applications from direct organ delivery to metabolite-mediated cross-organ communication, offering a holistic approach for complex diseases. Hence, this review summarizes recent advances in NDDS-mediated modulation of the Gut-X axis through intestinal targeting, establishing a conceptual framework for indirect multi-organ therapy. First, we outline the physiological mechanisms of the Gut-X axis, emphasizing the regulatory roles of gut microbiota and their metabolites in disease pathogenesis. Next, we systematically evaluate the advantages and limitations of NDDS in leveraging this axis for therapeutic intervention. We then discuss strategies to enhance gastrointestinal stability and targeted delivery of oral nanomedicines, followed by a comprehensive review of innovative NDDS approaches that exploit the Gut-X axis across diverse diseases, alongside emerging methodologies in the field. Finally, we critically examine the challenges and future directions in gut-centric nanomedicine to guide further research and clinical translation. Scheme 1 Graphical representation of the cross-organ regulation of the distal effects of oral nanomedicines, providing a novel and effective therapeutic strategy for diverse diseases. Created in BioRender. M, J. (2025) https://BioRender.com/bm238re. 2 Physiological Mechanisms and Pathological Implications of the Gut-X Axis The gut forms a bidirectional regulatory network with multiple organs through microbiota-mediated metabolic, immune, and neural signaling pathways, collectively termed the “Gut-X axis”. This network plays a pivotal role in maintaining physiological homeostasis, and its dysregulation can trigger systemic pathological alterations. In this section, we review the most extensively studied Gut-X axis pathways to elucidate their physiological mechanisms and pathological implications. 2.1 Gut-Brain Axis The Gut-Brain axis, the most extensively studied subsystem of the Gut-X axis, constitutes a multi-channel communication network between gut microbiota and the central nervous system (CNS). [41–43] This bidirectional interface involves neural, endocrine, and immune pathways (Figure 1). [44–46] Gut microbiota and their metabolites modulate neuroinflammation through diverse mechanisms. For instance, SCFAs cross the blood-brain barrier to suppress microglial overactivation, thereby supporting neural homeostasis. [47,48] Some bacteria, including Bifidobacterium, Lactobacillus, Bacteroides can directly influence Gamma-Aminobutyric Acid (GABA) receptors in the CNS to regulate neurotransmission for they can produce GABA or generate glutamate respectively. Furthermore, Lactobacillus can as well inhibit Indoleamine 2,3-Dioxygenase 1 activity, diminish neurotoxic quinolinic acid accumulation, elevate neuroprotective uric acid, and help rebalance neurotransmitters. The vagus nerve acts as a central conduit for Gut-Brain communication, relaying both mechanical (e.g., intestinal distension) and chemical (e.g., nutrient) signals to the nucleus tractus solitarius, thereby modulating CNS functions including those relevant to Multiple sclerosis. [47,49] The enteric nervous system (ENS), termed the “second brain”, interfaces with the CNS via vagal and spinal pathways. This system contributes to visceral nociception (e.g., in irritable bowel syndrome) and affective processing. [50–53] Microbiota-derived metabolites such as SCFAs foster regulatory T cell (Treg) differentiation, inhibit Th17 cell activation, and attenuate neuroinflammation driven by interleukin-17 (IL-17). Gut secretory IgA modulates can host-microbiota crosstalk by binding specific bacteria (e.g., segmented filamentous bacteria) within Peyer’s patches, thus reshaping systemic immune tone. Meanwhile, peripheral cytokines can exert neuromodulatory effects. Specifically, IL-1β can cross the blood-brain barrier and trigger microglial activation via the classic TREM2/DAP12 pathway, promoting processes such as amyloid-β clearance; tumor necrosis factor-α (TNF-α) can enhance hypothalamic neuronal excitability and promote depression-like behaviors. Disruption of the gut microbiota would compromise intestinal barrier integrity and release pro-inflammatory factors that activate the hypothalamic-pituitary-adrenal (HPA) axis. This activation could promote corticotropin-releasing hormone secretion, elevate cortisol levels, induce hippocampal impairment, and exacerbate stress responses. Imbalances in gut microbiota and associated metabolic disruptions are implicated in multiple brain disorders, including AD, Parkinson’s disease (PD), and depression. [50] Substantial evidence indicates that patients with AD exhibit significant alterations in gut microbial metabolism. [54] Notably, SCFAs help maintain neural homeostasis by suppressing microglial overactivation. [47,48] Certain bacterial metabolites, such as Lys phosphatidylcholine from Bacteroides ovale, can reduce amyloid burden and ameliorate AD pathology. [55] Conversely, lipopolysaccharide (LPS) can significantly promote the Amyloid-β (Aβ) deposition and the Tubulin-associated unit protein (Tau protein) phosphorylation via the TLR4/NF-κB pathway, thereby contributing to AD progression. [56] The marketed drug Ganlutein Capsules (GV-971) treats AD through a Gut-Brain axis mechanism rather than direct central action. [52] Simply put, GV-791 selectively inhibits pro-inflammatory bacteria (e.g., Enterobacteriaceae ) while enhancing beneficial flora, rebalancing the gut microbiota. It reduces peripheral phenylalanine and isoleucine accumulation, blocks infiltration of inflammatory immune cells into the brain, suppresses neuroinflammation, and attenuates both Aβ deposition and Tau phosphorylation, collectively improving cognitive function. [57] In PD, specific bacteria (e.g., Escherichia coli, Bacteroides, Akkermansia muciniphila ) and their metabolites may exacerbate disease via neuroinflammatory activation or direct modulation of brain activity. Environmental contaminants such as nanoplastics worsen PD pathology by disrupting microbial balance, particularly depleting SCFA-producing bacteria, and inducing intestinal barrier leakage. [51] Innovative strategies like antimicrobial nucleic acid vesicles delivered via the Gut-Brain axis show promise for PD treatment. [58] In depression, species including Lactobacillus rhamnosus and Bifidobacterium, along with metabolites like GABA and serotonin (5-HT), play key roles. [59] A study proposes to design polyGABA-based nanoparticles to deliver GABA in the gut. This approach has the potential to treat major depressive disorder via the GABA pathway. [60] Additionally, extracellular vesicles from Lepidium meyenii Walp have been shown to elevate 5-HT levels via microbiota-metabolic regulation, thereby alleviating depressive behaviors. [61] The Gut-Brain axis represents a complex bidirectional communication system, encompassing neural pathways (e.g., the vagus nerve and ENS, endocrine signaling (e.g., the HPA axis), immune interactions, and microbial metabolites such as SCFAs, neurotransmitters, bile acids, and LPS. Oral interventions leveraging this axis, including microbiome remodeling or nanocarrier-mediated delivery of metabolites/active compounds, enable precise modulation of the gut microenvironment. These strategies effectively regulate microbial composition, metabolic output, and immune activity, thereby ameliorating pathologies in distal brain regions and cognitive deficits. This mechanism establishes a novel therapeutic avenue for the prevention and treatment of neurodegenerative diseases. 2.2 Gut-Cancer Axis The Gut-Cancer axis, usually defined as a bidirectional interaction network between the gut microbiota and tumor initiation, progression and treatment response, deeply participates in shaping the tumor microenvironment through mechanisms such as metabolites, immune regulation, and genotoxicity. Pathogenic bacteria, such as Fusobacterium nucleatum, can disrupt host immune metabolism via metabolites like trimethylamine and its oxidized derivatives, thereby promoting tumor proliferation, metastasis, and chemotherapy resistance, for instance, through activation of the TLR4 autophagy pathway. [62] In contrast, beneficial bacteria such as Bifidobacterium have been shown to enhance anti-tumor immunity. Consequently, interventions targeting the gut microbiota hold promise for improving cancer treatment efficacy and reducing side effects. [63] For example, metformin not only increases the abundance of Bifidobacterium but also delays the progression of colorectal cancer. [64] What’s more, CBM588 is a marketed pharmaceutical compound which is composed primarily of viable Clostridium butyricum bacteria. It can promote the proliferation of intestinal beneficial bacteria ( bifidobacterium, lactobacillus, etc.), and also enhance the anticancer treatment effect of immune checkpoint inhibitors nivolumab and ipilimumab. [65] Thus, oral interventions targeting the gut microbiota demonstrate substantial anticancer potential. These strategies modulate key aspects of the Gut-Cancer axis, such as microbial composition, immune microenvironment, drug resistance, and specific molecular targets, by rebalancing microbiota, boosting antitumor immunity, overcoming resistance mechanisms, and enabling targeted delivery of anticancer agents. The use of innovative oral delivery systems (e.g., nanocarriers) allows precise manipulation of the microbiota and tumor microenvironment, improving treatment efficacy while minimizing systemic toxicity. This approach offers a promising and safe therapeutic avenue for cancer treatment. 2.3 Gut-Liver Axis The Gut-Liver axis, defined as a bidirectional regulatory network comprising the gut microbiota, the intestinal barrier as well as the liver, facilitates material exchange and signal transmission via the portal venous circulation (Figure 1). Its pathological mechanisms operate at three major levels: (1) metabolite-mediated regulation of hepatic homeostasis; (2) inflammatory responses triggered by microbial-associated molecular patterns; and (3) immune coordination and dysregulation between the gut and liver. [66] During gut dysbiosis, overgrowth of gram-negative bacteria elevates LPS release. Excess LPS activates kupffer cells via the TLR4/MyD88/NF-κB pathway, stimulating secretion of pro-inflammatory cytokines such as TNF-α and IL-6, and driving the progression of alcohol-associated liver disease. [67,68] Additionally, other gut-derived pathogenic factors contribute to liver injury. For example, lipoteichoic acid from enterococci activates hepatic toll-like receptor 2 signaling, promotes NACHT, LRR and PYD domains-containing protein 3 inflammasome assembly, and exacerbates lipid peroxidation and damage in non-alcoholic steatohepatitis (NASH). [69] SCFAs derived from microbiota have been shown to enter the liver via the portal vein. These SCFAs have been demonstrated to regulate glucose and lipid metabolism, while concomitantly inhibiting pro-inflammatory factors such as IL-6. This, in turn, has been shown to improve insulin resistance. [70] Secondary bile acids such as deoxycholic acid activate the hepatic farnesoid X receptor (FXR), suppressing NKT cell infiltration in hepatocellular carcinoma mediated by CXC motif chemokine 16. [70] Ammonia, generated from protein catabolism, accumulates and contributes to hepatic encephalopathy. Under dysbiosis, intestinal Th17 cells migrate to the liver via the CCL20/CCR6 axis and activate hepatic stellate cells through the IL-17A-JAK2/STAT3 pathway, promoting fibrosis. [71,72] In addition, fungal β-glucans, natural polysaccharides with immunomodulatory activity, can activate neutrophil extracellular traps via the Dectin-1 receptor upon entering the liver, exacerbating oxidative stress-induced damage in non-alcoholic fatty liver disease (NAFLD). [67] In light of these diverse mechanisms, oral therapies have evolved from broad-spectrum approaches (e.g., probiotics, antibiotics) to targeted strategies employing FXR agonists, TLR antagonists, and engineered bacteria. Metformin, an AMPK activator previously noted in Gut-Cancer axis modulation, also benefits Gut-Liver disorders. Alone, it increases Akkermansia abundance and butyrate production, alleviating dysbiosis in NAFLD/NASH patients. [73] Combined with probiotics, quercetin, or coumaric acid, metformin acts through multiple pathways including cAMP/AMPK/SIRT1 signaling. [74,75] Obeticholic acid, an FXR agonist, inhibits bile acid synthesis by activating ileal FXR and upregulating fibroblast growth factor 19. This reduces hepatic exposure to toxic bile acids and improves management of primary biliary cholangitis. [76] Rifaximin, a gut-targeted antibiotic, lowers blood ammonia by suppressing ammonia-producing bacteria, offering therapeutic benefit in hepatic encephalopathy. [76] Lanifibranor, a pan-PPAR-α/δ/γ agonist, enhances gut tight junction expression, reduces endotoxin translocation, and inhibits TLR4 signaling, thereby counteracting NASH fibrosis. [77] Resmetirom, a thyroid hormone receptor β (THR-β) agonist, promotes bile acid metabolism and reduces hepatic lipotoxicity, providing a therapeutic strategy for NASH. [78–80] Above all, by precisely targeting different nodes of the Gut-Liver axis (microbiome composition, metabolite profile, intestinal barrier, and specific receptors), these oral medications influence hepatic metabolic homeostasis, inflammatory responses, fibrosis progression, and immune responses. This offers an efficient and promising “Gut-Liver” targeted therapeutic approach for the prevention and treatment of major liver diseases such as NAFLD/NASH, primary biliary cholangitis, and hepatic encephalopathy. 2.4 Gut-Bone/Joint Axis The Gut-bone/joint axis is a dynamic field of research that profoundly reveals the close and complex relationship between the gut microbiota and skeletal joint health. Gut microbiota regulates bone and joint homeostasis through two primary mechanisms: (1) metabolic product-mediated nuclear receptor signaling, and (2) immune cell migration across tissues. Under physiological conditions, commensal bacteria such as Lactobacillus ferment dietary fiber to produce SCFAs. [81] SCFAs inhibit histone deacetylase, thereby suppressing osteoclast differentiation, and also reduce intestinal 5-HT levels, which promotes osteogenesis. [82] In pathological states such as osteoarthritis (OA), downregulation of intestinal FXR signaling disrupts bile acid metabolism, leading to elevated matrix metalloproteinase-13 (MMP-13) expression and accelerated joint degradation. Concurrently, an altered Firmicutes/Bacteroidetes ratio further diminishes SCFA production, impairing glucagon-like peptide-1 receptor (GLP-1R) activation and reducing inhibition of inflammatory factors driven through NF-κB pathway such as IL-1β and TNF-α (Figure 1). In rheumatoid arthritis (RA), pathogenic bacteria including Prevotella expand and activate intestinal Th17 cells. These cells migrate to the synovium via the CCL20/CCR6 axis and recruit neutrophils through IL-17-JAK/STAT signaling. Simultaneously, reduced Bifidobacterium levels compromise regulatory Treg differentiation, further exacerbating local inflammation due to impaired immunoregulation. [83] This dysregulation of the Gut-joint axis represents a core mechanism underlying metabolic-immune crosstalk in joint diseases. Several oral therapeutics have demonstrated efficacy in treating bone and joint disorders via the gut axis. Liraglutide, a GLP-1 receptor agonist, activates intestinal GLP-1R and reduces IL-1β-induced expression of iNOS, MMP-13, and ADAMTS-5, showing promise for OA treatment. [84] Lactoferrin, an iron-binding glycoprotein, modulates gut microbiota, e.g., enhancing Lactobacillus and Bifidobacterium, thereby elevating SCFA levels. Innovative lactoferrin-derived self-assembling nanoparticles have also been developed to systemically enhance bone regeneration via oral delivery, representing a pioneering peptide-based strategy for treating osteoporosis. [85] Additionally, tofacitinib (a JAK inhibitor) and romosozumab (an anti-sclerostin antibody) can inhibit IL-6 signaling, ameliorating RA symptoms, and modulate gut microbiota to activate the Wnt/β-catenin osteogenic pathway, thereby improving osteoporosis. [86] In summary, microbial metabolites (SCFAs/bile acids) influence bone joint diseases through a dual mechanism of regulating bone metabolism and promoting pro-inflammatory migration of immune cells (Th17/Treg). Nano-oral drugs offer three key advantages: targeted delivery (precision targeting of gut microbiota/immune cells), synergistic regulation (enhancing SCFA production while inhibiting NF-κB/JAK-STAT inflammation), and high efficacy and safety (enhancing local therapeutic effects while reducing systemic toxicity). These advantageous NDDS can exert their therapeutic effects simply by targeting the gut microbiota, without the need to overcome multiple physiological barriers, providing an innovative treatment strategy for bone and joint diseases. Figure 1. Graphical representation of the mechanisms of interaction between different Gut-X axes, identifying shared and distinct mechanisms linking gut to distal organs. Created in BioRender. M, J. (2025) https://BioRender.com/ahfkq3f. 2.5 Other Gut-X Axes The Gut-Kidney axis operates through a coordinated interplay of microbial composition, intestinal barrier permeability, and functional metabolites derived from gut microbiota. Uremic toxins, primarily indoxyl sulfate and p-cresyl sulfate, [87] and microbiota-derived SCFAs enter systemic circulation via the portal vein and directly affect renal tubular epithelial cells, contributing to kidney injury and even pulmonary fibrosis. [88] Increased gut permeability facilitates endotoxin translocation (e.g., LPS), which activates the Toll-like receptor 4/NF-κB pathway in the kidneys, promotes B cell class switching and excessive IgA production, and triggers IgA nephropathy. [89] Microbial antigen mimetics (e.g., molecular mimicry) can disrupt Th17/Treg balance and promote renal inflammation. Meanwhile, the kidneys help maintain intestinal homeostasis through the excretion of gut-derived toxins and synthesis of regulatory hormones, establishing a bidirectional crosstalk. Disruption of this communication can lead to severe complications including chronic kidney disease (CKD), end-stage renal disease, diabetic nephropathy, and septic acute kidney injury. [90] Within the Gut-Lung axis, gut microbiota modulate pulmonary immune homeostasis via metabolites such as SCFAs and tryptophan derivatives, primarily through dendritic cell migration and Th17/Treg balance regulation. [91] Dysbiosis exacerbates pulmonary inflammation via the TLR4/NF-κB pathway. [92,93] The Gut-Heart axis involves gut-originating hormones like liraglutide, which promotes atrial natriuretic peptide secretion via the GLP-1R/Epac2 pathway, influencing cardiovascular pathology. [94] Concurrently, systemic low-grade inflammation resulting from impaired intestinal barrier function suppresses brain-derived neurotrophic factor, contributing to cardiac injury. [95] In the Gut-Skin axis, dysbiosis-induced accumulation of gut-derived uremic toxins (e.g., p-cresyl sulfate) enters portosystemic circulation, activates skin TRPV1 channels and the keratinocyte IL-23/IL-17 axis, and compromises epidermal barrier integrity. [96] These axes share fundamental mechanisms, including gut mucosal immune regulation (e.g., IgA secretion), vagus nerve signaling, and systemic metabolite dissemination, highlighting the gut’s role as a “second brain” in systemic pathophysiology. A range of therapeutic agents, such as probiotic formulations (e.g., Lactobacillus/Bifidobacterium blends ), JAK inhibitors (e.g., tofacitinib), GLP-1 receptor agonists (including oral formulations like Rybelsus®), and oral carbon adsorbents (e.g., AST-120), have shown promise in treating skin disorders, asthma, cardiovascular diseases, and CKD through distinct Gut-X axis mechanisms. These findings open new avenues for repurposing oral medications in the treatment of cross-organ diseases. 3 Gut-X axis： Oral delivery shortcut for treating distal diseases Oral NDDS have been widely used to deliver various drugs, regulating the composition and metabolism of gut microbiota has become a target for the treatment of disease, [97] and the intestine is connected with many organs, using the Gut-X axis to treat diseases has become a direction for treating disease, [98,99] but oral NDDS reach the intestinal microenvironment to play a role is a complex process. The oral NDDS treats distal diseases through the Gut-X axis, the core is to use the intestine as the largest immune, metabolic and endocrine organ of the human body. It regulates the intestinal microecology, improves the intestinal barrier, and regulates gut-derived signals. Specific mechanisms such as molecules transmit drug effects to brain, liver, lungs, kidneys and other organs associated with the intestine, thereby intervening in distal diseases. NDDS act directly in the gut after oral administration, affecting remote organs by regulating gut microbiota, metabolites or local immunity, independent of ingredients leaving the intestinal lumen, but oral NDDS need to overcome multiple biological barriers to reach the designated location to utilize the Gut-X axis. In this process, several intestinal barriers are difficult to bypass, including gastrointestinal chemical environment barriers, intestinal absorption barriers and intestinal microbial barriers. [100,101] 3.1 Drug delivery barriers for Gut-X axis-targeting therapy 3.1.1 Gastrointestinal chemical environment barrier After the oral NDDS enters the gastrointestinal tract, it must first face the complex and harsh environmental test in the gastrointestinal tract, which poses multiple threats to its structural stability and functional integrity. Pepsin, as an acidic protease with high activity in stomach, will not only degrade protein and polypeptide carrier materials directly, but also destroy the target ligands (such as antibody fragments and target peptides) modified on the surface of NDDS, making them lose their specific recognition ability. [102] In addition, the stomach generates continuous mechanical shear force through strong peristaltic movement, which may lead to collision and aggregation between nanoparticles, or even direct fragmentation, while the instability of gastric emptying rate (influenced by feeding status, food properties, etc.) further aggravate the risk of retention and degradation. [103] After entering the small intestine, the environmental changes bring new challenges. The pH in the small intestine changes gradually from 5.0-6.0 in the duodenum to 6.5-7.5 in the ileum. This pH fluctuation will change the ionization state of the nanoparticles surface groups and affect their surface charge distribution. At the same time, high concentrations of electrolytes in intestinal fluid (e.g. Na⁺, K⁺, Ca²⁺, etc.) may destroy the colloidal stability of nanoparticles through charge neutralization, ion bridging, etc., resulting in aggregation or precipitation of NDDS. For example, divalent Ca²⁺ can bind to phosphate groups on the surface of liposomes and initiate liposome fusion. More importantly, there are a large number of digestive enzymes in the small intestine. Trypsin, pancreatic lipase and pancreatic amylase secreted by pancreas will degrade protein, lipid and carbohydrate carriers respectively. Peptidase and glycosidase secreted by brush border of intestinal epithelial cells will further decompose the modifying molecules on the surface of carriers. These enzymatic hydrolysis actions will not only destroy the carrier structure and lead to early leakage of drugs, but also change the physicochemical properties of NDDS, making them lose their targeting and transmembrane transport capabilities. [104] To further reach intestinal target sites, oral NDDS must overcome gastrointestinal environment chemical barriers, which necessitates enhancing their stability and transport efficiency in the complex gastrointestinal environment. For instance, pH-sensitive carrier materials such as polylactic acid, poly (lactic acid-co-glycolic acid) or chitosan derivatives are used for the strongly acidic environment of the stomach, [105] they can avoid hydrolysis of polymer chains or fragmentation of liposome phospholipids under low pH conditions in the stomach, and also use anionic polymers such as sodium alginate as an outer barrier to isolate gastric acid corrosion by virtue of its gelation characteristics under acidic conditions. At the same time, in order to resist the mechanical shear of stomach, it is necessary to optimize the mechanical strength of the carrier, for example, to reduce the fragmentation or aggregation caused by peristalsis by using a polymer network or rigid nanostructure with high crosslinking degree, to prolong the retention time of NDDS in gastric mucosa by surface modification bioadhesive materials such as polylysine, to avoid being cleared before reaching the intestinal cavity due to too fast gastric emptying, or to design a small particle size system for fasting state, and to accelerate the entry into the small intestine by utilizing the negative correlation between gastric emptying rate and particle size. After entering the small intestine, facing the influence of pH fluctuation and ionic strength, a pH/electrolyte dual-responsive carrier can be designed, in which the drug is coated with an inner pH-sensitive polymer and the outer layer is modified with polyethylene glycol. Under the neutral environment of the small intestine, the outer layer is depolymerized, and the inner layer triggers the release of the drug due to the increase of pH, so as to avoid premature disintegration of the carrier. At the same time, the electrolyte-induced aggregation is reduced by surface charge regulation, for example, the nanoparticles are electrically neutral by polyethylene glycol modification. Or the copolymer with side chain amino group moderately protonated under neutral condition can be selected to form hydration layer to resist bridging effect of divalent ions. [106] 3.1.2 Intestinal mucus-epithelial barrier through Gut-X axis-targeting therapy The core of the oral NDDS through the Gut-X axis is to act locally in the intestine, rather than directly acting on distal organs through systemic blood circulation, so it is necessary to avoid excessive absorption of drugs into the bloodstream and ensure that drugs can contact intestinal targets such as gut microbiota and intestinal mucosa. Intestinal mucus layer is a gelatinous polysaccharide-protein complex covering the surface of intestinal epithelial cells. It is composed of mucin and glycoprotein, etc. It forms a dense inner layer and a loose outer layer. The inner mucus layer is free of bacteria and closely attached to intestinal epithelium. The outer mucus layer is composed of gut microbiota, enzymes and immune cells. After oral NDDS enter the intestine, they must first break through the mucus layer to contact the intestinal epithelial cells or gut microbiota below, which is an important obstacle for the NDDS to access the intestinal epithelial cells. [107,108] It plays a protective role in the intestine to prevent the invasion of foreign substances and provide habitat for intestinal microorganisms. The structural characteristics of molecules can cause multiple retention effects on NDDS, with positively charged nanoparticles being easily adsorbed by negatively charged mucins due to electrostatic attraction, hydrophobic carriers possibly binding to hydrophobic domains of mucins, and nanoparticles with larger particle sizes being difficult to penetrate due to the screening effect of mucus pores. [109] In addition, the mucus layer is continuously renewed through secretion, which will remove adsorbed nanoparticles with the passage of mucus, further hindering its contact with intestinal epithelium. The high viscosity and rapid clearance rate of the mucus layer limit the residence time of NDDS in the intestinal tract, the dynamic renewal and dense structure of the intestinal mucus layer prevents nanoparticles from contacting epithelial cells, thereby affecting drug delivery efficiency, and may also hinder the movement of NDDS, making it difficult for them to reach target sites. [110] The core of overcoming intestinal absorption barriers by oral NDDS lies in reducing non-specific interactions with mucus layers, enhancing penetration, and countering the dynamic clearance mechanisms of mucus. For electrostatic adsorption and hydrophobic binding of mucin in the mucus layer, hydrophilic modification can be carried out on the surface of NDDS, such as introducing flexible hydrophilic chains such as polyethylene glycol or polyethylene oxide. These chains can form a dense hydration layer on the surface of nanoparticles, reduce electrostatic attraction between negatively charged mucin and nanoparticles through steric hindrance and charge shielding effect, and reduce hydrophobic interaction between mucin hydrophobic domain and carrier. Prevent NDDS from being trapped in mucus networks to enhance NDDS penetration. [111] To fully account for the clearance of the mucus layer, studies have been conducted to use mucus to destroy the surface-modified layer, exposing surface-modified lipids, overcoming the mucus barrier and increasing cellular uptake. [112,113] Additionally, surface-modified mucin penetrating peptides TAT peptides, RGD peptides, or virus-derived penetration sequences are also effective strategies to direct NDDS to move along pores of mucus networks by binding specifically to glycosyl-domains in mucins, or to increase penetration efficiency by changing the spatial conformation of mucins to open temporary channels. In order to resist the dynamic renewal of mucus layer, it is necessary to prolong the effective action time of NDDS in mucus layer. NDDS with dual functions of biological adhesion and penetration can be designed. For example, unfolded protein chains can physically interact and entangle with mucin, while amino acids interact with mucus through hydrogen bonds and disulfide bonds, which can prolong the retention time of NDDS on mucous membrane to achieve the balance of ’adhesion and slow penetration. [114–116] 3.1.3 Intestinal microbial-metabolic barrier for Gut-X axis-targeting therapy Intestinal microflora is an important barrier for Gut-X axis-based oral NDDS. Intestinal microflora can regulate the integrity of intestinal barrier and is an important protective barrier against pathogens. The imbalance of intestinal microflora may lead to the impairment of intestinal barrier function. [117] While microbiota may impair the intestinal barrier or disrupt drug delivery, [118] NDDS can also modulate the intestinal barrier by regulating gut microbiota composition or altering the local barrier structure to increase permeability. In addition, gut microbiota may affect the efficacy of NDDS by regulating the host immune system. Some flora metabolites (such as SCFA) can enhance the immune response. [119] Symbiotic bacteria may degrade drugs or competitively consume drug delivery carriers, which affects the penetration efficiency of NDDS. Various specific enzymes secreted by bacteria are one of the key factors to destroy NDDS. Intestinal bacteria can metabolize the modified components on the surface of nanoparticles by secreting enzymes, thus changing their structure and bioavailability, thus affecting the absorption of nanoparticles. [120] For example, the esterase produced by Bifidobacterium can precisely act on the ester bonds in polymer carriers such as polylactic acid-glycolic acid copolymers, causing hydrolysis reactions, which in turn lead to the collapse of the carrier structure; β-glucosidase secreted by Escherichia coli will target those nanoparticles modified by glycosyl groups and destroy the glycosyl structure on their surface, which not only affects the targeting of NDDS, but also causes drug release in advance. Meanwhile, various products produced by bacterial metabolism will also have adverse effects on NDDS. SCFA (such as acetic acid, propionic acid, etc.) are typical representatives, which will change the pH value of local intestinal microenvironment and lead to aggregation or disintegration. In addition, Some bacteria also secrete toxins or specific proteins, which may interact with nanoparticles in a non-specific manner, causing aggregation and even disintegration of nanoparticles, seriously weakening the drug delivery function of NDDS and hindering drug action in intestinal lumen (Figure 2). Figure 2 . Oral NDDS cross gastrointestinal chemical hurdles, absorption obstacles, and microbial barriers via multiple tactics. Created in BioRender. M, J. (2025) https://BioRender.com/a60kjf5. 3.2 Progress in Gut-X axis Targeted Therapy 3.2.1 Regulation of intestinal microenvironment One of the mechanisms of oral drugs to treat distal diseases through the Gut-X axis is to regulate intestinal microecology. The core is to accurately reshape the flora structure by orally delivering probiotics, prebiotics, metagenes, engineered microbial preparations or yeast cell wall-coated nanoenzymes, etc. with gut microbiota as the target. On the one hand, NDDS can regulate the composition of gut microbiota, selectively promote the proliferation of beneficial bacteria such as Lactobacillus, Bifidobacterium, and Akkermansia muciniphila, and inhibit pathogenic bacteria such as Escherichia coli and Clostridium . [121,122] Overgrowth, restore the symbiotic balance of the flora and enhance diversity; On the other hand, by regulating intestinal immune cells (such as macrophages and T cells), [123] regulate the secretion balance of pro-inflammatory factors such as TNF-α and IL-6 and anti-inflammatory factors such as IL-10, repair damaged intestinal mucosal barrier, restore local and systemic immune homeostasis of intestinal tract, and reduce adverse effects of intestinal inflammation or immune disorder. [124] During this process, the metabolism of flora will produce active substances such as SCFAs, GABA and bile acid metabolites. These substances not only regulate intestinal function locally, but also extend the positive regulatory effect to distal organs through nerve conduction (such as vagus nerve pathway) and body fluid transportation (such as blood circulation) of Gut-X axis together with regulated intestinal microecology. For example, sustained release of GABA following colonization of the gut by orally engineered Lactobacillus plantarum alleviates anxiety-like behavior, and yeast cell-wall encapsulated nanoenzymes reduce systemic inflammation levels while restoring flora diversity [125] . 3.2.2 Improve the intestinal barrier Another core link of oral drug intervention in distal lesions through the Gut-X axis is to ’repair and strengthen intestinal barrier’. Gut microbiota can regulate the integrity of intestinal barrier and is an important protective barrier against pathogens. The imbalance of flora may lead to impaired intestinal barrier function. [117] Oral NDDS loads active ingredients such as mucosal repair agents and immunomodulators, which can repair and strengthen intestinal barrier damaged by inflammation, oxidative stress and bacterial toxins. The intestinal epithelial barrier is composed of tightly connected intestinal epithelial cells that are connected by tight junction proteins.(such as Claudin-1, Occludin and Zonula occludens-1) are interconnected to form a continuous and tight selective permeable physical barrier whose primary function is to protect the gut from harmful substances while allowing the absorption of nutrients that, [126] when breached, exacerbate sepsis and hyperglycaemia. [127] Components released by oral NDDS promote the expression and proper assembly of tight junction proteins in intestinal epithelial cells, repair damaged epithelial cell structures, reduce epithelial cell gaps, strengthen the integrity of intestinal physical barriers, [128–130] and prevent pathogens (e.g. bacteria, viruses) and toxins (e.g. LPS) from entering the blood circulation through epithelial gaps; [131] On the other hand, against the intestinal immune barrier, the system can regulate intestinal mucosal immune cells (e.g. macrophages, dendritic cells, T lymphocytes), [123] promoting anti-inflammatory factors secretion of (e.g. IL-10), inhibition of pro-inflammatory factors (such as TNF-α and IL-6), balance the immune microenvironment of intestinal mucosa, enhance the ability of immune barrier to recognize and eliminate pathogens, and further block the adhesion and translocation of pathogens. [132] After the intestinal physical and immune barriers are effectively repaired, the translocation of pathogens will be blocked, thus reducing the entry of gut-derived toxins into the blood and inflammatory signal transmission, reducing systemic inflammatory response, and improving non-alcoholic fatty liver, liver fibrosis, asthma, chronic obstructive pulmonary disease and other diseases. [133] 3.2.3 Regulation of gut-derived signaling molecules Gut microbiota and its metabolites can act as signaling molecules to affect distal organ function through the Gut-X axis. Oral NDDS release loaded active regulatory ingredients after precise arrival in the gut (such as signal molecule modulators, enzyme inhibitors, receptor agonists, etc.), and rely on the Gut-X axis cross-organ regulatory network to achieve precise regulation of gut-derived signal molecules and cross-system bioactive information transmission, and then intervene in remote diseases. On the one hand, signaling molecules that regulate metabolism of gut microbiota (such as SCFA, bile acids, tryptophan metabolites, etc.), such as promoting the synthesis of SCFA with anti-inflammatory and immune regulating functions by beneficial bacteria, [134] reducing pro-inflammatory signal molecules such as lipopolysaccharide produced by harmful bacteria, and optimizing the balance of liver-intestinal circulation of bile acids; [135] On the other hand, it interferes with hormone signaling molecules secreted by endocrine cells in the intestine Cytokine signaling molecules (e.g. glucagon-like peptide-1, cholecystokinin) that interact with immune cells in the gut (such as TNF-α, IL-10), by inhibiting the over-expression of pro-inflammatory cytokines, regulate intestinal hormone levels, maintain intestinal local signal homeostasis [136] . These regulated gut-derived signaling molecules are transported through Gut-X axis neurotransmission (e.g. vagus pathway) and body fluids.(such as blood circulation, lymphatic circulation) and other ways to transmit bioactive information to remote organs such as brain, liver, lungs, kidneys, etc. For example, intestinal microbiota can regulate key proteins to affect gene expression and neuronal pathways in the brain, improve various neurodegeneration by preventing oxidative stress, and thus affect key biomarkers in the process. The gut-brain axis has shown great potential in a variety of neurological diseases, including AD and depression. [137] 4 NDDSs-Mediated Disease Intervention via the Gut-X Axis In contemporary medicine, the advent of NDDS has heralded a revolutionary shift in therapeutic approaches. Conventional drug therapies are often hampered by issues. NDDS, however, offer novel solutions through their precise targeting capabilities and efficient drug release mechanisms. Within a deeper understanding of the interactions between multiple organs, particularly the Gut-X axis, the potential of NDDS in multi-organ combined therapy has gradually come to light. In the context of multi-organ therapy, NDDS are commonly employed to modulate the gut microbiota and its metabolites, thereby indirectly treating diseases. Additionally, an emerging class of drug delivery strategies aims to bypass systemic circulation by “hitching a ride” on the Gut-X axis to transport therapeutics to distant target organs. The following sections will delve into the specific applications of NDDS in multi-organ therapy and the challenges they face. 4.1 Direct Intestinal Targeting When exploring the application of NDDS in multi-organ therapy, it is essential to first address their potential for direct intestinal targeting. Direct intestinal targeting NDDS primarily focus on modulating the gut microbiota and its metabolites to improve gut health and indirectly affect distal organs. This type of NDDS has shown great potential in treating gastrointestinal diseases and systemic diseases closely related to the gut microbiota. 4.1.1 NDDSs Targeting Gut Microbiota and Its Metabolites for Brain Disease The Gut-Brain axis represents a critical pathway through which the gastrointestinal tract influences brain function and behavior. Recent advancements in nanotechnology have led to the development of NDDS that can exploit this axis to treat various brain disorders. These systems leverage the intricate communication between the gut and brain, often mediated by the gut microbiota and its metabolites, to enhance the efficacy of therapeutic agents. By targeting the gut, these NDDS offer a distinct advantage over conventional point-to-point brain targeting approaches, as they circumvent the formidable blood-brain barrier and associated systemic delivery challenges, thereby achieving more effective modulation of neuroinflammation, restoration of neurotransmitter balance, and potential alleviation of neurological disease symptoms such as AD, sleep disturbances, and depression. In this paradigm, the NDDS does not enter the systemic circulation but acts locally within the intestinal lumen to remodel the gut microbiota, prompting the production of bioactive microbial metabolites. These metabolites are subsequently absorbed into the bloodstream and transported to the brain, where they exert their therapeutic effects. This approach effectively circumvents the long-standing challenge of bypassing the BBB for drug delivery in the treatment of brain diseases via the Gut-Brain axis. It enables indirect modulation of distal brain function through oral administration and local action in the gut. A representative example involves oral administration of chiral gold nanoparticles (L-Au NPs). Their rigid structure confers resistance to the harsh gastrointestinal environment, ensuring predominant retention within the gut. Research demonstrates that the therapeutic benefits of L-Au NPs are not mediated by their own translocation to the brain. Instead, they specifically target gut microbes (e.g., Clostridium and Lactobacillus ) via electrostatic interactions and upregulate key enzymes in the microbial tryptophan metabolic pathway. This enhancement significantly increases the microbial conversion of dietary tryptophan into indole-3-acetic acid (IAA). Following its absorption, IAA efficiently crosses the BBB. Within the brain, it activates the aryl hydrocarbon receptor (AHR), leading to the suppression of NLRP3 inflammasome activation in microglia and astrocytes. Consequently, this mechanism significantly alleviates neuroinflammation, reduces amyloid-β (Aβ) deposition and tau pathology, and ultimately improves cognitive function in AD mouse models. [138] Similarly, a NDDS based on honokiol (Nano-HO), an extract from Magnolia officinalis, exerts therapeutic effects on cognitive deficits in AD model mice (TgCRND8). Nano-HO modulates the composition and structure of the gut microbiota, thereby safeguarding the stability of the intestinal microbial community. By ameliorating gut dysbiosis, Nano-HO indirectly influences brain function, thus exerting a therapeutic effect on AD. Additionally, Nano-HO inhibits Aβ deposition, tau hyperphosphorylation, and neuroinflammation while regulating the JNK/CDK5/GSK-3β signaling pathway, thereby improving cognitive deficits. This multi-target intervention strategy enables Nano-HO to comprehensively impact the pathophysiological processes of AD. [139] A novel quercetin (Que)-based nanotherapeutic platform (QNP@HMs) was developed for targeted intestinal delivery by encapsulating quercetin nanoparticles (QNPs) within chitosan-calcium alginate hydrogel microspheres, where the chitosan component was thiolated (chitosan-SH) to enable formation of disulfide bonds with mucin proteins in the colonic mucus layer, thereby significantly enhancing mucoadhesion and prolonging local residence time (Figure 3A). Que repaired the intestinal barrier, modulated the composition of gut microbiota, increased the abundance of SCFA-producing bacteria, and reduced pro-inflammatory bacteria. These effects subsequently influenced the CNS through metabolites (e.g., GABA, 5-HT) or immune pathways (Figure 3B-C). In summary, QNP@HMs could ameliorate high-altitude sleep disturbance via the Gut-Brain axis. [140] An engineered Lactococcus lactis strain, based on an upconversion optogenetic micro-nano system, is used to regulate brain function via the Gut-Brain axis. The engineered L. lactis is encapsulated in pH-sensitive sodium alginate microspheres, which release the bacteria in the alkaline environment of the intestines, thereby achieving small intestine targeting. Additionally, the surface of the microspheres is modified with small intestine targeting antibodies (PepT1), further enhancing the accumulation in the small intestine. The engineered L. lactis is designed to express specific bioactive molecules (such as GABA, GCSF, and GLP1) upon illumination with blue light or near-infrared light. These bioactive molecules reach the brain via the bloodstream and regulate brain function. This system not only modulates the gut microbiota but also enables precise control of brain function through optogenetic technology. [47] The Gut-Brain axis also plays a crucial role in irritable bowel syndrome (IBS). The nanostructures assembled from berberine (BBR) and baicalin (BA), namely BA-BBR NPs, exhibit synergistic therapeutic effects on diarrhea-predominant irritable bowel syndrome (IBS-D). BA-BBR NPs improve the intestinal microenvironment by modulating the gut microbiota and suppressing intestinal inflammation. Moreover, they indirectly influence brain function by regulating brain-gut peptides within the Microbiota-Gut-Brain axis (e.g., decreasing levels of 5-HT, vasoactive intestinal peptide, and choline acetyltransferase in serum and colonic tissues). This results in the alleviation of common psychiatric symptoms in IBS-D patients, such as anxiety and depression. The multi-target intervention on the Microbiota-Gut-Brain axis enables BA-BBR NPs to effectively ameliorate a variety of symptoms in IBS-D patients, including diarrhea, visceral hypersensitivity, and psychiatric symptoms (Figure 3D). [141] Figure 3 Oral NDDSs overcome barriers, target the gut, and indirectly modulate brain states by rebalancing the gut microbiota. (A) QUE was primarily released in simulated colonic fluid (SCF) while remaining stable in simulated gastric fluid (SGF), indicating that QNP@HMS possesses specific and targeted drug release characteristics. (B) Regulation of gut microbiota by QNP@HM. (C) QNP@HMs reversed the gut microbiota changes of the relative abundance and species diversity due to high-altitude hypoxia. Reprinted with the permission from Ref. [140] . Copyright © 2024 Asian Network Scientific Information-Ansinet. (D) BA-BBR NPs modulate gut microbiota to alter colonic and serum levels of brain-gut peptides 5-HT, VIP and CHAT, thereby indirectly influencing brain function. Reprinted with the permission from Ref. [141] . Copyright © 2020 Frontiers Media S.A. In summary, the application of NDDS for treating brain diseases via the Gut-Brain axis holds significant promise. These systems offer a non-invasive approach to modulate brain function by targeting the gut microbiota, thereby influencing neuroinflammation and neurotransmitter levels. 4.1.2 NDDS for Cancer Therapy by Modulating Gut Microbiota and Its Metabolites The Gut-Cancer axis describes how gut microbiota and their metabolites remotely shape tumor immunity and therapy response. Colorectal cancer (CRC) initiation, progression and immune evasion are tightly linked to gut dysbiosis. Therefore, engineering oral NDDS that first remain stable throughout the gastrointestinal tract and then precisely reprogram tumor-associated microbiota and their metabolites has emerged as one of the most clinically translatable strategies. M13@Ag employs phage-display technology to isolate an M13 filamentous phage that selectively binds the pro-tumorigenic bacterium Fusobacterium nucleatum (Fn). Silver nanoparticles (AgNP) are subsequently electrostatically assembled on the capsid surface to generate a “phage-capsid-AgNP” bioinorganic hybridization system. Capsid proteins specifically recognize Fn surface receptors, enabling pathogen-targeted and selective bacterial clearance. Concurrently, the phage coat directly activates dendritic cells (DCs) and M1-polarized macrophages, thereby remodeling the tumor immune microenvironment (Figure 4A). [142] In another approach, commercial probiotic Clostridium butyricum spores serve as the core onto which dextran (Dex) is covalently grafted via host-guest β-cyclodextrin chemistry, prepared “spore-Dex” and can be further loaded with capecitabine and diclofenac. The Dex shell enhances intestinal adhesion, promotes fermentation by C. butyricum, and thereby generates abundant anti-cancer SCFAs. The facile chemical modification of the prebiotic also enables co-therapy with payload drugs. Importantly, spore-Dex systematically remodels the gut microbiota, shifting its composition from a pro-tumorigenic to an anti-tumorigenic state. [143] Similarly, a prebiotic xylan-stearic acid conjugate is used as a scaffold to link the prodrug capecitabine (SCXN). Upon reaching the colon, the xylan backbone is specifically degraded by gut microbiota (e.g., Bacteroides ), triggering controlled release of capecitabine. This modulation of local microbiota indirectly reshapes the tumor microenvironment by enhancing anti-tumor immunity and suppressing pro-inflammatory bacteria (Figure 4B-C). [144] Additionally, NDDS are now engineered to enhance chemotherapy efficacy by boosting systemic antitumor immunity. Oral nanoarmored live bacterial biotherapeutics (supraLBT) are delivered via the oral route to target the gut barrier, protecting the gut microbiota and intestinal epithelial cells (IECs) from the cytotoxic damage of chemotherapeutic agents. By modulating the gut microbiota and their metabolites—such as SCFAs and secondary bile acids—supraLBT indirectly activates systemic immunity (e.g., promoting CD8+ T cell infiltration into tumors), thereby achieving cross-organ (Gut-Tumor) synergistic therapy. [145] Figure 4 Distinct NDDS achieve efficient colon targeting via diverse strategies and exert CRC treatment by modulating the gut microbiota. (A) M13@Ag, which exhibits exceptional Fn-binding capacity, enables highly efficient CRC tissue targeting for the selective eradication of bacteria. Reprinted with the permission from Ref. [142] . Copyright © 2020 American Association for the Advancement of Science. (B) SCXN increases the intra-tumoral drug accumulation. (C) The modulation by SCXN on the activity of probiotics is supposed to promote the production of SCFA in colon. Reprinted with the permission from Ref. [144] . Copyright © 2023 Springer Nature. 4.1.3 NDDS for the Treatment of other Diseases via Modulating Gut Microbiota and Its Metabolites Beyond the Gut-Brain axis and Gut-Cancer axis, the Gut-Liver axis the gastrointestinal tract plays a pivotal role in influencing the health of various other organs and systems through what can be termed as Gut-X axis. NDDS have emerged as a powerful tool to harness these interactions, offering targeted therapies for systemic diseases. By modulating the gut microbiota and its metabolic output, NDDS can exert therapeutic effects on conditions ranging from cardiovascular diseases to metabolic disorders. The Gut-Liver axis plays a pivotal role in hepatic fibrosis pathogenesis. Low molecular weight chitosan selenium nanoparticles (LCS-SeNPs) with a chitosan shell resist degradation by gastric acid and digestive enzymes, ensuring intact drug delivery to the colon. By modulating intestinal barrier function and gut microbiota, their metabolites alleviate high-fat diet-induced NAFLD (Figure 5A). [146] For IgA nephropathy, a novel oral drug delivery system, NYPs@Gel, is composed of budesonide-loaded yeast microcapsules (NYPs) and pectin gel. The yeast microcapsules target the gut-associated lymphoid tissue by binding their surface β-glucans to the Dectin-1 receptor on intestinal immune cells, thereby inhibiting the production of intestinal IgA. The pectin gel prolongs the retention time of the formulation in the intestines, provides sustained drug release, and modulates the gut microbiota to enhance the intestinal mucosa’s resistance to inflammation. The combination of yeast microcapsules with pectin gels creates a multifunctional drug delivery system that modulates the Gut-Kidney axis while minimizing systemic toxicity. [147] Additionally, dexamethasone sodium phosphate (DexP) was encapsulated into extracellular vehicles (EVs) derived from orange juice to develop a nanoparticle platform (EVs-DexP). Upon oral administration, these nanoparticles were taken up by lymphocytes in the ileocecal region, particularly targeting dendritic cells and monocytes in Peyer’s patches (Figure 5B). By modulating the gut immune response to indirectly alleviate renal pathological damage, EVs-DexP demonstrates the cross-organ therapeutic effect of the Gut-Kidney axis (Figure 5C). [148] Emerging evidence highlights a strong correlation between osteoporosis and gut microbiota dysbiosis. Propolis has the potential to modulate the gut microbiota, but its stability and bioavailability in the gastrointestinal tract are relatively low. To address this issue, researchers have developed propolis nanoemulsions (PNEs) to enhance their stability and bioavailability. PNEs first come into contact with intestinal epithelial cells in the gut. Studies have shown that PNEs can effectively penetrate the intestinal mucus layer and enter intestinal epithelial cells via endocytosis. Compared with unmodified propolis, the mucus penetration rate of PNEs is about 9 times higher, demonstrating better gastrointestinal absorption capacity. PNEs can modulate the structure of the gut microbiota, reduce the abundance of Streptococcus, thereby lowering the levels of inflammatory factors and inhibiting the formation and function of osteoclasts. PNEs also affect bone metabolism by modulating the metabolites of the gut microbiota, particularly by increasing the level of L-arginine. [149] The “lung-large intestine exterior-interior relationship” is a fundamental concept in Traditional Chinese Medicine, and the lung-intestine axis can be regarded as an extension of this theory. The spatiotemporal biotherapeutic system (CaO₂@PCS@BC spores) was constructed by encapsulating probiotic spores of Bacillus coagulans (BC) with a polydopamine/chitosan (PCS) nanocoating and combining them with CaO₂ nanoparticles. Upon oral administration, CaO₂@PCS@BC spores penetrate the intestinal mucus barrier, alleviates local hypoxia, and restores gut microbiota balance, ultimately mitigating viral pneumonia symptoms via the Gut-Lung axis. By restoring gut SCFA production and ATP levels, the system downregulated pulmonary pro-inflammatory cytokines (e.g., TNF-α, IL-1β) while enhancing antiviral responses (e.g., IFN-β), demonstrating the Gut-Lung axis’s role in systemic immunity. [150] Probiotic-derived extracellular vesicles (LF216EV) from Limosilactobacillus fermentum SLAM216 are orally administered and absorbed via the intestinal epithelium or Peyer’s patches. LF216EV administration altered gut microbiota composition and elevated serum 5-HT levels, which subsequently modulated skin immune responses and improved atopic dermatitis symptoms via the Gut-Skin axis. LF216EV reduced epidermal thickness and mast cell infiltration in DNCB-induced atopic dermatitis mice by downregulating pro-inflammatory cytokines (IL-6, TNF-α) and upregulating 5-HT receptor HTR2C. [151] Selenium, a vital antioxidant, shields cells from oxidative stress-induced damage through its antioxidant properties. Nano-selenium (NanoSe), a selenium supplement encapsulated in nanoparticle form, has been shown to improve several indices associated with male fertility, including sperm count, vitality, and motility. Moreover, NanoSe can regulate the gut microbiota, which may influence overall health and fertility. The regulatory effect of NanoSe on the gut microbiota may enhance systemic immune status by influencing the composition and function of the gut microbiota. A healthy gut microbiota is closely linked to robust immune function, and such immune enhancement may contribute to improved fertility. [152] Figure 5 (A) Potential pathways through which LCS-SeNPs alleviate NAFLD and associated metabolic disorders in HFD-fed mice. Reprinted with the permission from Ref. [146] . Copyright © 2024 Multidisciplinary Digital Publishing Institute. (B) EVs-DexP are taken up by CD4⁺ T cells, CD11b⁺ dendritic cells, and CD11c⁺ macrophages in the jejunum and ileum, attenuate intestinal IgA⁺ lymphocytes and IgA synthesis, and thereby exert cross-organ therapeutic effects against IgA nephropathy. (C) Effect of EVs-DexP on IgA + lymphocytes immunophenotype in Peyer’s patches . Reprinted with the permission from Ref. [148] . Copyright © 2022 Frontiers Media S.A. In conclusion, NDDS offer a transformative drug delivery paradigm by precisely targeting the gut microenvironment to indirectly regulate distal organs via the Gut-X axis. Their key advantages lie in their ability to overcome conventional delivery barriers through gut-restricted action, enhanced local retention, and controlled modulation of microbial and metabolic pathways-all achieved without requiring systemic exposure of the nanocarriers themselves. This approach significantly improves therapeutic specificity and safety while minimizing off-target effects. 4.2 Cross-Organ Delivery of NDDS through Gut-X Axis Following an in-depth investigation of NDDS applications for intestinal targeting in multi-organ therapy, an emerging class of trans-organ delivery approaches have been reported. These NDDS platforms exploit ”hitchhiking” mechanisms via intestinal immune cells or neuronal pathways to significantly enhance both drug delivery efficiency and therapeutic outcomes. Silver nanomaterials (Ag NMs) are directly translocated from the gut to the CNS via peripheral nerve fibers, bypassing the traditional blood circulation route. Specifically, when Ag NMs enter the gastrointestinal tract through oral administration, they adsorb proteins to form a nano-corona that facilitates the uptake of Ag NMs by various cell subsets of the gut, especially enterocytes and enteric nerve cells in the submucosal/myenteric plexus (Figure 6A). After being taken up by enterocytes, Ag NMs may enter the submucosa through transcellular or paracellular pathways and are subsequently taken up by enteric nerve cells (Figure 6B-D). The vagus and spinal nerves mediate the translocation of Ag NMs from the gut to the brain and spinal cord, respectively (Figure 6E-F). This transneuronal transport of Ag NMs from the gut to the CNS indicates that, in addition to the blood barrier, Ag NMs can hitch a ride on nerve fibers to reach distant target organs, overcoming the physiological barriers traditionally considered. [153] Capsaicin (Cap) specifically binds to the TRPV1 receptor, which is highly expressed on primary sensory neurons in the gastric mucosa. By conjugating Cap to the surface of piezoelectric barium titanate (BTO) particles to form BTO@Cap, the particles precisely target TRPV1-positive nerve endings in the gastric mucosa. BTO, as a piezoelectric material, converts mechanical forces from gastric peristalsis into electrical pulses. These electrical signals stimulate TRPV1-expressing afferent nerves, transmitting signals to the hypothalamus via the vagus nerve-mediated Gut-Brain axis. This process modulates appetite and energy metabolism by inhibiting neuropeptide Y neurons and activating pro-opiomelanocortin neurons, ultimately reducing food intake and enhancing energy expenditure. [154] Co-delivery of tamoxifen (TAM) and sulforaphane (SFN) in nanostructured lipid carriers (TAM-SFN-NLCs) is achieved via oral administration, targeting the intestinal barrier. Thes carriers enhance drug absorption from the gastrointestinal lumen via lymphatic transport, reducing first-pass metabolism. They facilitate drug transfer from the intestine through organ delivery into the bloodstream, ultimately reaching tumor tissues. [155] Given the abundance of gut microbiota in the pancreatic tumor microenvironment, commensal bacteria from the gut can spontaneously migrate from the gut to pancreatic tumor tissues. Anaerobic bacteria are attracted by the hypoxic environment of the tumor tissue, while aerobic bacteria are drawn to the relatively higher pH of the pancreatic tissue. Leveraging the natural migration characteristics of gut commensal bacteria, a probiotic spore-based oral drug delivery system (SPORE-MGEM) was developed by conjugating mesoporous silica nanoparticles loaded with gemcitabine (MGEM) to Bacillus subtilis spores. The spores used in SPORE-MGEM exhibit high resilience and biocompatibility. They can maintain stability in the harsh gastrointestinal environment and regain activity upon reaching the tumor tissue. This characteristic enables SPORE-MGEM to effectively reach and accumulate in tumor tissues after oral administration, where the released gemcitabine can effectively inhibit tumor cell proliferation and induce apoptosis. This innovative platform utilizes the gut−pancreas axis to translocate target drugs from the gut to pancreatic tumors, thereby increasing intratumoral drug accumulation by approximately threefold. [156,157] A non-invasive oral prodrug delivery system, which combines β-glucan with the anticancer drug temozolomide, forms prodrug nanoparticles (prodrug NPs) that can be specifically targeted by intestinal M cells and subsequently engulfed by macrophages. These NPs are specifically targeted by intestinal M cells and subsequently taken up by local macrophages via phagocytosis or hitchhike. The macrophages-hitchhiked prodrug transported to the circulatory system via the lymphatic system, ultimately crossing the blood-brain barrier to reach glioma sites. [158] Figure 6 (A) Working model of the transneuronal transport of NPs from the gut to the CNS. (B) Representative SEM and EDX images of Ag NMs isolated from the gut, brain, and spinal cord of mice. Scale bars, 100 nm. (C) Representative confocal microscopy images of the transfer of Ag NPs from gut epithelial cells (Caco-2) to neurons (DRG). Scale bars, 4 μm. (D) Schematic illustration of the cellular uptake and transfer process of Ag NPs from gut epithelial cells to peripheral neurons. (E) Representative light sheet microscope images showing the Ag NP transmission inside the vagus nerve (green, Ag NPs). (F) Ag NPs and Ag NWs were detected in the spinal nerves of rhesus monkeys treated orally with Ag NMs, including the cervical spinal nerves, thoracic nerves, and lumbar spinal nerves. Reprinted with the permission from Ref. [153] . Copyright © 2023 American Association for the Advancement of Science. In summary, NDDS represent a transformative advancement in Gut-X axis-mediated cross-organ therapeutics. These systems can be designed to directly target the gastrointestinal tract to modulate the gut microbiota and its metabolites, thereby improving gastrointestinal health and indirectly influencing distant organs. Moreover, NDDS can exploit ”hitchhiking” mechanisms to overcome various physiological barriers, and utilize biological transport mechanisms to exert therapeutic effects on distant target organs. This dual approach not only enhances the specificity and efficacy of drug delivery but also minimizes potential side effects, making nanoparticles a promising tool for the treatment of a wide range of diseases. Table 1 NDDS for treating diseases via the Gut-X axis | l-Au NP | Not mentioned | AD | Gut-Brain | Modulate microbiota; Increase the levels of the tryptophan metabolite IAA | [138] | | Nano-HO | Not mentioned | AD | Gut-Brain | Modulate microbiota and metabolites | [139] | | QNP@HMs | Chitosan-calcium alginate hydrogel microspheres | Sleep disturbance | Gut-Brain | Modulate microbiota and metabolites | [140] | | Engineered L. lactis | pH-sensitive sodium alginate microspheres | Anxiety and PD | Gut-Brain | Modulate microbiota and metabolites | [47] | | BA-BBR NPs | Not mentioned | IBS | Gut-Brain | Modulate microbiota and suppression of intestinal inflammation; regulation of brain-gut peptides | [141] | | M13@Ag | Not mentioned | CRC | Gut-Cancer | Eliminate protumoral bacteria | [142] | | Spores-dex | Not mentioned | CRC | Gut-Cancer | Increase SCFA-producing bacteria | [143] | | SCXN | Xylan backbone | CRC | Gut-Cancer | Modulate microbiota and metabolites | [144] | | supraLBT | Phenolic nanoarmor microbial coating | Breast Cancer | Gut-Cancer | Modulate intestinal epithelial cells; Modulation of metabolites | [145] | | LCS-SeNPs | Chitosan shell | NAFLD | Gut-Liver | Modulate microbiota and metabolites | [146] | | NYPs@Gel | Pectin gel | IgA nephropathy | Gut-Kidney | Modulate microbiota and metabolites | [147] | | EVs-DexP | Extracellular vehicles | IgA nephropathy | Gut-Kidney | Modulate microbiota and gut immune response | [148] | | PNEs | Modified propolis | Osteoporosis | Gut-Bone | Modulate microbiota, metabolites and inflammatory factors | [149] | | CaO₂@PCS@BC spores | PCS nanocoating | Viral pneumonia | Gut-Lung | Modulate microbiota and metabolites | [150] | | LF216EV | Extracellular vesicles | Atopic dermatitis | Gut-Skin | Modulate microbiota and metabolites | [151] | | NanoSe | Not mentioned | Reproductive disorders | Gut- Reproductive | Influence the composition and function of the gut microbiota | [152] | | Ag NMs | “Hitchhiking” peripheral nerve fibers | Brain diseases | Gut-Brain | Not mentioned | [153] | | BTO@Cap | Stimulate afferent nerves | Obesity | Gut-Brain | Modulate appetite and energy metabolism | [154] | | TAM-SFN-NLCs | Lymphatic transport | Cancer | Gut-Cancer | Not mentioned | [155] | | SPORE-MGEM | Bacillus subtilis spores | Pancreatic tumor | Gut- Pancreatic | Inhibit tumor cell proliferation and induce apoptosis | [157] | | Prodrug NPs | “Hitchhiking” macrophages | Glioma | Gut-Brain | Not mentioned | [158] | 5 Conclusions and Future Prospects This review explores the intricate crosstalk between the gut microbiota and the host immune-metabolic networks, and summarizes recent advances in Gut-X axis-targeted therapeutic strategies employing novel various drug delivery systems for extraintestinal disease. Various intestinal microorganisms can influence the physiological processes in organs throughout the body and disease development through the production of bile acids, choline, SCFA, neurotransmitters, small molecules, toxins, inflammatory factors, and so on, significantly impacting health and disease through metabolites, immune signals, and neural signals. At the same time, extra-intestinal organs can also influence the gut microbiota compositional and functional, indicating that all Gut-X axes are bidirectional. Precise utilization of gut microbiota offers a promising avenue for combating diseases. However, despite its therapeutic promise, significant challenges hinder the clinical application of Gut-X axis-targeted drug delivery systems. Key limitations include incomplete mechanistic understanding of Gut-X axis interactions, substantial interindividual variability in microbiota composition, inefficient cross-barrier drug delivery, and translational issues of nanomedicines. The Gut-X axis involves multiple levels and mechanisms. Microbial metabolites can regulate host physiology through neural, immune, endocrine and other pathways, but the dynamic interaction of the multi-signal network remains unclear. Meanwhile, due to the interactive effects of multiple aspects such as host genetic background (e.g., gene mutations), microbiota diversity (e.g., differences in gut microbiota gene abundance and metabolic profiles), and disturbances in the dynamic environment (e.g., diet structure, circadian rhythm), there are significant individual differences in the regulation of the Gut-X axis. How can universal treatment be achieved? As a complex multi-component ecosystem, the gut faces multiple biological barriers in targeted regulation. The complex environment in the gut has a certain impact on the stability of drugs. For example, the dynamically changing pH gradient, digestive enzyme activity, and microbial metabolites in the gut may lead to the degradation or functional inactivation of drug molecules. Due to the existence of the intestinal epithelial barrier, it is difficult for macromolecules and nanoparticles (>200 nm) to be delivered across the membrane, significantly reducing the targeting efficiency. The hydrophobic interaction between endogenous substances in the gut (e.g., bile salts, dietary lipids) and the delivery system may cause non-targeted aggregation, reducing the bioavailability. In clinical use, the conversion rate of nanomedicines is extremely low due to defects in standardized production, poor predictability of animal models, and heterogeneity of clinical responses. In the future, for the NDDS to play a more extensive role in treating various extra-intestinal diseases, the above problems must be overcome. The ternary integration of nanotechnology, AI, and biology is a promising new research direction. The development of modern AI has provided opportunities for the clinical application of nanomedicines. For example, combining spatial multi-omics technology and in-situ nano sensors with AI modeling can reveal the spatio-temporal interaction patterns at the microbiota-host interface to clarify the pathological mechanisms of the Gut-X axis; using AI to develop adaptive nanorobots (which release drugs dynamically in response to inflammatory factors) can promote the treatment of gut - related diseases from a “one-size-fits-all” approach to an era of “precise regulation”; using AI to optimize microfluidic synthesis can control the standard deviation of nanoparticle size within 5% to improve the conversion rate of nanomedicines. Although there are still many problems in the application of nanomedicines in the Gut-X axis, we believe that by ingeniously utilizing AI, further deepening the mechanism research, and carefully designing multi-organ synergistic targeted nanomedicines, the drug delivery system can systematically address the above challenges, achieving a new dimension of cross-organ therapy for the Gut-X axis and providing transformative treatment strategies for metabolic diseases, neuropsychiatric disorders, etc.

[1] X. Lin, Z. Yu, Y. Liu, C. Li, H. Hu, J.C. Hu, M. Liu, Q. Yang, P. Gu, J. Li, K. S. Nandakumar, G. Hu, Q. Zhang, X. Chen, H. Ma, W. Huang, G. Wang, Y. Wang, L. Huang, W. Wu, N.N. Liu, C. Zhang, X. Liu, L. Zheng, P. Chen, iMeta 2025, 4, e270.[2] X. Liu, Y. Chen, S. Zhang, L. Dong, J. Exp. Clin. Cancer Res. CR 2021, 40, 221.[3] F. Boem, G. P. Greslehner, J. P. Konsman, L. Chiu, Front. Neurosci. 2023, 17, 1172783.[4] M.G. Gwak, S.Y. Chang, Immune Netw. 2021, 21, e20.[5] R. He, P. Qi, L. Shu, Y. Ding, P. Zeng, G. Wen, Y. Xiong, H. Deng, J. Exp. Clin. Cancer Res. CR 2025, 44, 44.[6] K. E. Hays, J. M. Pfaffinger, R. Ryznar, Gut Microbes 2024, 16, 2393270.[7] G. Xie, R. Jiang, X. Wang, P. Liu, A. Zhao, Y. Wu, F. Huang, Z. Liu, C. Rajani, X. Zheng, J. Qiu, X. Zhang, S. Zhao, H. Bian, X. Gao, B. Sun, W. Jia, EBioMedicine 2021, 66, 103290.[8] R. A. Dongoran, F.C. Tu, C.H. Liu, Tzu Chi Med. J. 2023, 35, 290.[9] C. Michaudel, H. Sokol, Cell Metab. 2020, 32, 514.[10] T. Doifode, V. V. Giridharan, J. S. Generoso, G. Bhatti, A. Collodel, P. E. Schulz, O. V. Forlenza, T. Barichello, Pharmacol. Res. 2021, 164, 105314.[11] M. Zhuang, X. Zhang, J. Cai, Gut Microbes 2024, 16, 2387800.[12] Y. He, L. Fu, Y. Li, W. Wang, M. Gong, J. Zhang, X. Dong, J. Huang, Q. Wang, C. R. Mackay, Y.-X. Fu, Y. Chen, X. Guo, Cell Metab. 2021, 33, 988.[13] Q. Yang, B. Wang, Q. Zheng, H. Li, X. Meng, F. Zhou, L. Zhang, Adv. Sci. Weinh. Baden-Wurtt. Ger. 2023, 10, e2207366.[14] J. Suez, N. Zmora, G. Zilberman-Schapira, U. Mor, M. Dori-Bachash, S. Bashiardes, M. Zur, D. Regev-Lehavi, R. Ben-Zeev Brik, S. Federici, M. Horn, Y. Cohen, A. E. Moor, D. Zeevi, T. Korem, E. Kotler, A. Harmelin, S. Itzkovitz, N. Maharshak, O. Shibolet, M. Pevsner-Fischer, H. Shapiro, I. Sharon, Z. Halpern, E. Segal, E. Elinav, Cell 2018, 174, 1406.[15] W. Jia, G. Xie, W. Jia, Nat. Rev. Gastroenterol. Hepatol. 2018, 15, 111.[16] B. Y. S. Kim, J. T. Rutka, W. C. W. Chan, N. Engl. J. Med. 2010, 363, 2434.[17] M. A. Younis, H. M. Tawfeek, A. A. H. Abdellatif, J. A. Abdel-Aleem, H. Harashima, Adv. Drug Deliv. Rev. 2022, 181, 114083.[18] C. Gao, Z. Yang, R. Song, H. Sheng, L. Zhu, Int. J. Pharm. 2025, 673, 125375.[19] H. Wang, F. Zhou, M. Shen, R. Ma, Q. Yu, Int. J. Nanomedicine 2025, 20, 1383.[20] J. Long, X. Liang, Z. Ao, X. Tang, C. Li, K. Yan, X. Yu, Y. Wan, Y. Li, C. Li, M. Zhou, Acta Biomater. 2024, 188, 27.[21] M. Zhang, D. Merlin, Inflamm. Bowel Dis. 2018, 24, 1401.[22] W.H. Chou, T. Lühmann, L. Meinel, J. O. Morales, Nanopharmaceuticals: Principles and Applications Vol. 3 . 2020, 271–315.[23] J. N. Chu, G. Traverso, Nat. Rev. Gastroenterol. Hepatol. 2022, 19, 219.[24] F. Laffleur, A. H. Mayer, Expert Opin. Drug Deliv. 2023, 20, 1595.[25] M. Azman, A. H. Sabri, Q. K. Anjani, M. F. Mustaffa, K. A. Hamid, Pharm. Basel Switz. 2022, 15, 975.[26] R. Kumar, T. Islam, M. Nurunnabi, J. Control. Release Off. J. Control. Release Soc. 2022, 351, 504.[27] T. C. Ezike, U. S. Okpala, U. L. Onoja, C. P. Nwike, E. C. Ezeako, O. J. Okpara, C. C. Okoroafor, S. C. Eze, O. L. Kalu, E. C. Odoh, U. G. Nwadike, J. O. Ogbodo, B. U. Umeh, E. C. Ossai, B. C. Nwanguma, Heliyon 2023, 9, e17488.[28] J. Gao, J. M. Karp, R. Langer, N. Joshi, Chem. Mater. Publ. Am. Chem. Soc. 2023, 35, 359.[29] E. Blanco, H. Shen, M. Ferrari, Nat. Biotechnol. 2015, 33, 941.[30] R. Yang, T. Wei, H. Goldberg, W. Wang, K. Cullion, D. S. Kohane, Adv. Mater. Deerfield Beach Fla 2017, 29, 10.1002/adma.201606596.[31] Y. Qiao, C. He, Y. Xia, D. K. W. Ocansey, F. Mao, Autoimmun. Rev. 2025, 24, 103717.[32] R. Balakrishnan, S.-I. Kang, J.-Y. Lee, Y.-K. Rho, B.-K. Kim, D.-K. Choi, Aging Dis. 2024, 0.[33] T. Luo, Q. Che, Z. Guo, T. Song, J. Zhao, D. Xu, Front. Pharmacol. 2024, 15, 1442854.[34] J. R. Turner, Nat. Rev. Immunol. 2009, 9, 799.[35] X. Ouyang, Y. Liu, K. Zheng, Z. Pang, S. Peng, Asian J. Pharm. Sci. 2024, 19, 100883.[36] J. Guo, X. Pan, Q. Wu, P. Li, C. Wang, S. Liu, H. Zhang, Z. Huang, X. Mou, H. Liu, J. Xue, Signal Transduct. Target. Ther. 2025, 10, 1.[37] P. Garbati, C. Picco, R. Magrassi, P. Signorello, L. Cacopardo, M. Dalla Serra, M. G. Faticato, M. De Luca, F. Balestra, M. P. Scavo, F. Viti, Pharmaceutics 2024, 16, 431.[38] Y. Zhang, Y. Wang, Y. Lu, H. Quan, Y. Wang, S. Song, H. Guo, J. Nanobiotechnology 2025, 23, 400.[39] Y. Ren, W. Wu, X. Zhang, Acta Pharm. Sin. B 2023, 13, 2544.[40] A. M. Hasan, S. Cavalu, A. Y. Kira, R. S. Hamad, M. A. Abdel-Reheim, E. A. Elmorsy, A. F. El-kott, K. Morsy, A. S. AlSheri, S. Negm, S. Saber, Int. J. Nanomedicine 2025, 20, 741.[41] Q. You, F. Liang, G. Wu, F. Cao, J. Liu, Z. He, C. Wang, L. Zhu, X. Chen, Y. Yang, Adv. Mater. 2024, 36, 2306583.[42] S. M. Collins, M. Surette, P. Bercik, Nat. Rev. Microbiol. 2012, 10, 735.[43] G. Agirman, E. Y. Hsiao, Cell 2021, 184, 2524.[44] J. Dong, L. Xu, A. Qu, C. Hao, M. Sun, C. Xu, S. Hu, H. Kuang, Adv. Mater. 2025, 37, 2418723.[45] L. W. Yu, G. Agirman, E. Y. Hsiao, Annu. Rev. Immunol. 2022, 40, 143.[46] W. Cui, Z. Guo, X. Chen, R. Yan, W. Ma, X. Yang, Y. Lin, Sci. Bull. 2024, 69, 3925.[47] H. Pan, T. Sun, M. Cui, N. Ma, C. Yang, J. Liu, G. Pang, B. Liu, L. Li, X. Zhang, W. Zhang, J. Chang, H. Wang, ACS Nano 2022, 16, 6049.[48] N. L. Ritz, L. A. Draper, T. F. S. Bastiaanssen, C. J. R. Turkington, V. L. Peterson, M. Van De Wouw, K. Vlckova, C. Fülling, K. E. Guzzetta, A. Burokas, H. Harris, M. Dalmasso, F. Crispie, P. D. Cotter, A. N. Shkoporov, G. M. Moloney, T. G. Dinan, C. Hill, J. F. Cryan, Nat. Microbiol. 2024, 9, 359.[49] J. Dong, L. Xu, A. Qu, C. Hao, M. Sun, C. Xu, S. Hu, H. Kuang, Adv. Mater. 2025, 37, 2418723.[50] G. Agirman, K. B. Yu, E. Y. Hsiao, Science 2021, 374, 1087.[51] X. Liang, G. Huang, Y. Wang, N. Andrikopoulos, H. Tang, F. Ding, Y. Li, P. C. Ke, ACS Nano 2025, 19, 5475.[52] H.-S. Lee, E. Lobbestael, S. Vermeire, J. Sabino, I. Cleynen, Gut 2020, gutjnl.[53] J. Aguilera-Lizarraga, H. Hussein, G. E. Boeckxstaens, Nat. Rev. Immunol. 2022, 22, 674.[54] T. Zhang, G. Gao, L.Y. Kwok, Z. Sun, Gut Microbes 2023, 15 .[55] Y. Fan, O. Pedersen, Nat. Rev. Microbiol. 2021, 19, 55.[56] X. Guo, C. Li, J. Zhang, M. Sun, J. Xu, C. Xu, H. Kuang, L. Xu, Nat. Aging 2023, 3, 1415.[57] X. Wang, G. Sun, T. Feng, J. Zhang, X. Huang, T. Wang, Z. Xie, X. Chu, J. Yang, H. Wang, S. Chang, Y. Gong, L. Ruan, G. Zhang, S. Yan, W. Lian, C. Du, D. Yang, Q. Zhang, F. Lin, J. Liu, H. Zhang, C. Ge, S. Xiao, J. Ding, M. Geng, Cell Res. 2019, 29, 787.[58] W. Cui, Z. Guo, X. Chen, R. Yan, W. Ma, X. Yang, Y. Lin, Sci. Bull. 2024, 69, 3925.[59] J. Feng, Q. Cen, Y. Cui, X. Hu, M. Li, L. Wang, J. Wei, N. Sun, J. Wang, A. Zhang, Pharmacol. Res. 2025, 211, 107541.[60] B. D. Tri, B. Shashni, H. Matsui, Y. Nagasaki, J. Controlled Release 2023, 360, 110.[61] R. Hong, L. Luo, L. Wang, Z. Hu, Q. Yin, M. Li, B. Gu, B. Wang, T. Zhuang, X. Zhang, Y. Zhou, W. Wang, L. Huang, B. Gu, S. Qi, iMeta 2023, 2, e116.[62] L.Y. Zhao, J.X. Mei, G. Yu, L. Lei, W.H. Zhang, K. Liu, X.L. Chen, D. Kołat, K. Yang, J.K. Hu, Signal Transduct. Target. Ther. 2023, 8, 201.[63] E.J. Han, J.S. Ahn, Y.J. Choi, D.H. Kim, J.S. Choi, H.J. Chung, Biochim. Biophys. Acta Rev. Cancer 2025, 1880, 189251.[64] L. Song, Y. Hao, C. Wang, Y. Han, Y. Zhu, L. Feng, L. Miao, Z. Liu, J. Controlled Release 2022, 350, 922.[65] N. Dizman, L. Meza, P. Bergerot, M. Alcantara, T. Dorff, Y. Lyou, P. Frankel, Y. Cui, V. Mira, M. Llamas, J. Hsu, Z. Zengin, N. Salgia, S. Salgia, J. Malhotra, N. Chawla, A. Chehrazi-Raffle, R. Muddasani, J. Gillece, L. Reining, J. Trent, M. Takahashi, K. Oka, S. Higashi, M. Kortylewski, S. K. Highlander, S. K. Pal, Nat. Med. 2022, 28, 704.[66] C. L. Hsu, B. Schnabl, Nat. Rev. Microbiol. 2023, 21, 719.[67] J. R. Hov, T. H. Karlsen, Nat. Rev. Gastroenterol. Hepatol. 2023, 20, 135.[68] B. Eksteen, Clin. Liver Dis. 2016, 20, 1.[69] J. Deng, Y. Hu, P. Zhu, Y. Yu, Q. Chen, H. Wu, Z. Zha, H. Wang, Y. Ma, ACS Nano 2025, 19, 10500.[70] O. Pabst, M. W. Hornef, F. G. Schaap, V. Cerovic, T. Clavel, T. Bruns, Nat. Rev. Gastroenterol. Hepatol. 2023, 20, 447.[71] B. Zhang, X. Fan, H. Du, M. Zhao, Z. Zhang, R. Zhu, B. He, Y. Zhang, X. Li, J. Li, N. Gu, ACS Nano 2023, 17, 6081.[72] S. Xiang, Y. Lan, L. Lu, C. Sun, Y. Lai, Z. Mai, F. Tian, E. Fu, H. Zhong, F. Cui, H. Mao, C. Song, Biosens. Bioelectron. 2023, 225, 115082.[73] Y. Sun, H. Zhang, X. Gong, Y. Li, R. Han, C. Zhou, J. Han, Sci. Rep. 2025, 15, 22699.[74] S. H. Seif el-Din, M. Salem, N. El-Lakkany, O. Hammam, S. Nasr, H. Okasha, L. Ahmed, S. Saleh, S. Botros, Hum. Exp. Toxicol. 2021, 40, 1496.[75] H. Afshari, S. Noori, A. Zarghi, Iran. J. Pharm. Res. IJPR 2023, 22, e136952.[76] K. Kjærgaard, K. Frisch, M. Sørensen, O. L. Munk, A. F. Hofmann, J. Horsager, A. C. Schacht, M. Erickson, D. Shapiro, S. Keiding, J. Hepatol. 2021, 74, 58.[77] P. Caraceni, V. Vargas, E. Solà, C. Alessandria, K. De Wit, J. Trebicka, P. Angeli, R. P. Mookerjee, F. Durand, E. Pose, A. Krag, J. S. Bajaj, U. Beuers, P. Ginès, for the Liverhope Consortium, Hepatology 2021, 74, 1660.[78] M. P. Cooreman, J. Butler, R. P. Giugliano, F. Zannad, L. Dzen, P. Huot-Marchand, M. Baudin, D. R. Beard, J.-L. Junien, P. Broqua, M. F. Abdelmalek, S. M. Francque, Nat. Commun. 2024, 15, 3962.[79] Y. Hao, Z. Hao, X. Zeng, Y. Lin, J. Gastroenterol. 2024, 59, 788.[80] S. Sookoian, C. J. Pirola, Cell 2024, 187, 2897.[81] Y. Yang, C. Hao, T. Jiao, Z. Yang, H. Li, Y. Zhang, W. Zhang, M. Doherty, C. Sun, T. Yang, J. Li, J. Wu, M. Zhang, Y. Wang, D. Xie, N. Wang, X. Huang, C. Li, F. J. Gonzalez, C. Xie, C. Zeng, G. Lei, Science 2025, 388(6742), eadt0548.[82] Y. Zhao, M. Cheng, L. Zou, L. Yin, C. Zhong, Y. Zha, X. Zhu, L. Zhang, K. Ning, J. Han, Gut 2022, 71, 1041.[83] R. Li, Z. Miao, Y. Liu, X. Chen, H. Wang, J. Su, J. Chen, Adv. Sci. 2024, 11, 2307971.[84] F. Berenbaum, C. Meurot, L. Sudre, K. Bismuth, R. Rattenbach, P. Denefle, C. Martin, C. Jacques, Ann. Rheum. Dis. 2021, 80, 417.[85] S. Pal, M. Sayeed, A. Kumar, D. P. Verma, M. K. Harioudh, N. K. Verma, K. Porwal, S. Sharma, C. Kulkarni, A. Bandyopadhyay, M. N. Mugale, K. Mitra, J. K. Ghosh, N. Chattopadhyay, ACS Appl. Mater. Interfaces 2021, 13, 17300.[86] M. Dougados, C. Charles-Schoeman, Z. Szekanecz, J. T. Giles, S. R. Ytterberg, D. L. Bhatt, G. G. Koch, I. Vranic, J. Wu, C. Wang, K. Kwok, S. Menon, C. A. Connell, A. Yndestad, J. L. Rivas, M. H. Buch, Ann. Rheum. Dis. 2023, 82, 575.[87] L. Pan, H. Yu, J. Fu, J. Hu, H. Xu, Z. Zhang, M. Bu, X. Yang, H. Zhang, J. Lu, J. Jiang, Y. Wang, Acta Pharm. Sin. B 2023, 13, 1537.[88] H. Watanabe, Y. Miyamoto, D. Honda, H. Tanaka, Q. Wu, M. Endo, T. Noguchi, D. Kadowaki, Y. Ishima, S. Kotani, M. Nakajima, K. Kataoka, S. Kim-Mitsuyama, M. Tanaka, M. Fukagawa, M. Otagiri, T. Maruyama, Kidney Int. 2013, 83, 582.[89] A. Sun, Q. Luo, H. Liu, W. Yang, J. Liu, X. Shi, Y. Nie, J. Sun, M. Sun, L. Liu, Nano Today 2025, 61, 102572.[90] L. Giordano, S. M. Mihaila, H. Eslami Amirabadi, R. Masereeuw, Trends Biotechnol. 2021, 39, 811.[91] K. F. Budden, S. L. Gellatly, D. L. A. Wood, M. A. Cooper, M. Morrison, P. Hugenholtz, P. M. Hansbro, Nat. Rev. Microbiol. 2017, 15, 55.[92] A. S. Neish, A. T. Gewirtz, H. Zeng, A. N. Young, M. E. Hobert, V. Karmali, A. S. Rao, Science 2000, 289(5484), 1560-1563.[93] A. J. Ratner, E. S. Lysenko, M. N. Paul, J. N. Weiser, Proc. Natl. Acad. Sci. 2005, 102, 3429.[94] A. Buglioni, J. C. Burnett, Nat. Med. 2013, 19, 534.[95] Q. Li, X. S. Zhong, S. S. Krishnachaitanya, M. Liu, R. Ou, Y. Xiao, D. W. Powell, K. Fujise, Eur. Heart J. 2023, 44, ehad655.3076.[96] M. Rios-Carlos, D. Cervantes-García, L. E. Córdova-Dávalos, L. G. Bermúdez-Humarán, E. Salinas, Gut Microbes 2024, 16, 2430420.[97] Y. Gao, D. Kong, J. Sun, Z. Ma, G. Wang, X. Ma, L. Sun, H. Luo, Y. Xu, K. Wang, Eur. J. Med. Res. 2025, 30, 226.[98] L. Zhao, J. Chen, B. Bai, G. Song, J. Zhang, H. Yu, S. Huang, Z. Wang, G. Lu, Front. Pharmacol. 2024, 14 .[99] B. Maddiboyina, Ramaiah, R. K. Nakkala, H. Roy, Chem. Biol. Drug Des. 2023, 102, 377.[100] B. Jiang, Y. Zhao, Y. Cao, C. Sun, W. Lu, Y. Fang, J. Agric. Food Chem. 2024, 72, 3291.[101] M. F. Neurath, D. Artis, C. Becker, Lancet Gastroenterol. Hepatol. 2025, 10, 573.[102] M. Wang, C. Wang, S. Ren, J. Pan, Y. Wang, Y. Shen, Z. Zeng, H. Cui, X. Zhao, Int. J. Mol. Sci. 2022, 23, 3362.[103] L.Z. Zhang, R.J. Du, D. Wang, J. Qin, C. Yu, L. Zhang, H.D. Zhu, Int. J. Nanomedicine 2024, 19, 9889.[104] L. de O. Macedo, J. F. Masiero, N. A. Bou-Chacra, Pharmaceutics 2024, 16, 1141.[105] C. Angulo, V. Sanchez, K. Delgado, E. Monreal-Escalante, L. Hernández-Adame, M. Angulo, M. Tello-Olea, M. Reyes-Becerril, Microb. Pathog. 2022, 169, 105648.[106] Z. Tian, Y. Mai, T. Meng, S. Ma, G. Gou, J. Yang, AAPS PharmSciTech 2021, 22, 179.[107] M. J. Kozieł, M. Ziaja, A. W. Piastowska-Ciesielska, Toxins 2021, 13, 758.[108] R. Okumura, K. Takeda, Semin. Immunopathol. 2024, 47, 2.[109] L. J. Kubiatowicz, N. Pourafzal, A. T. Zhu, Z. Guo, R. H. Fang, L. Zhang, Small Methods 2025, e2500624.[110] M. Tan, Y. Wang, Y. Ji, R. Mei, X. Zhao, J. Song, J. You, L. Chen, X. Wang, Talanta 2024, 275, 126172.[111] U. Kart, A. Raimbekova, S. Yegorov, G. Hortelano, Pharmaceutics 2025, 17, 609.[112] F. Veider, K. Zöller, A. Saleh, A. Bernkop-Schnürch, Int. J. Pharm. 2024, 651, 123817.[113] T. Pho, J. A. Champion, ACS Appl. Mater. Interfaces 2022, 14, 51697.[114] T. Zhang, L. Li, S. Chunta, W. Wu, Z. Chen, Y. Lu, J. Controlled Release 2023, 354, 146.[115] Y. Huang, J. Wang, V. Mancino, J. Pham, C. O’Grady, H. Li, K. Jiang, D. Chin, C. Poon, P.-Y. Ho, G. Gyarmati, J. Peti-Peterdi, K. R. Hallows, E. J. Chung, PNAS nexus 2024, 3(5), 187.[116] M. Lei, Q. Chen, Y. Wang, G. Wang, J. Drug Deliv. Sci. Technol. 2024, 95, 105651.[117] H.Z. Gou, Y.L. Zhang, L.F. Ren, Z.J. Li, L. Zhang, Front. Microbiol. 2022, 13, 929346.[118] Y. Lee, N. Kamada, J. J. Moon, Adv. Drug Deliv. Rev. 2021, 179, 114021.[119] A. T. Rahman, J. Shin, C.H. Whang, W. Jung, D. Yoo, C. Seo, B.-K. Cho, S. Jon, ACS Nano 2023, 17, 10996.[120] J. Qiao, R. Chen, M. Wang, R. Bai, X. Cui, Y. Liu, C. Wu, C. Chen, Nanoscale 2021, 13, 8806.[121] A. Sousa, A. A. M. Kämpfer, R. P. F. Schins, F. Carvalho, E. Fernandes, M. Freitas, Nanotoxicology 2025, 19, 141.[122] J. Lin, Y. Wei, X. Gu, M. Liu, M. Wang, R. Zhou, D. Zou, L. Yin, C. Zhou, D. Hu, J. Controlled Release 2025, 377, 93.[123] S. Yang, L. Fan, L. Yin, Y. Zhao, W. Li, R. Zhao, X. Jia, F. Dong, Z. Zheng, D. Zhao, J. Wang, J. Nanobiotechnology 2025, 23 .[124] J. Lao, S. Yan, Y. Yong, Y. Li, Z. Wen, X. Zhang, X. Ju, Y. Li, Microorganisms 2024, 12, 1379.[125] Z. Shi, X. Li, J. Chen, Z. Dai, Y. Zhu, T. Wu, Q. Liu, H. Qin, Y. Zhang, H. Chen, Bioact. Mater. 2024, 35, 167.[126] M. van der Zande, A. J. Kokalj, D. J. Spurgeon, S. Loureiro, P. V. Silva, Z. Khodaparast, D. Drobne, N. J. Clark, N. W. van den Brink, M. Baccaro, C. A. M. van Gestel, H. Bouwmeester, R. D. Handy, Environ. Sci. Nano 2020, 7, 1874.[127] Y.F. Wang, J.W. Li, D.P. Wang, K. Jin, J.J. Hui, H.Y. Xu, Drug Des. Devel. Ther. 2022, 16, 1697.[128] Y. Song, Y. Li, W. Hu, F. Li, H. Sheng, C. Huang, X. Gou, J. Hou, J. Zheng, Y. Xiao, Burns Trauma 2024, 12, tkad054.[129] C. Yang, K. Sharma, R. J. Mow, E. Bolay, A. Srinivasan, D. Merlin, Cell. Mol. Gastroenterol. Hepatol. 2024, 18, 101333.[130] O. R. Guadarrama-Escobar, P. Serrano-Castañeda, E. Anguiano-Almazán, A. Vázquez-Durán, M. C. Peña-Juárez, R. Vera-Graziano, M. I. Morales-Florido, B. Rodriguez-Perez, I. M. Rodriguez-Cruz, J. E. Miranda-Calderón, J. J. Escobar-Chávez, Int. J. Mol. Sci. 2023, 24, 4289.[131] H.Y. Nie, J. Ge, G.X. Huang, K.G. Liu, Y. Yue, H. Li, H.G. Lin, T. Zhang, H.F. Yan, B.X. Xu, H.W. Sun, J.W. Yang, S.Y. Si, J.L. Zhou, Y. Cui, Front. Physiol. 2024, 15 .[132] J. Zhuang, Z. Zhuang, B. Chen, Y. Yang, H. Chen, G. Guan, Mol. Med. 2025, 31 .[133] D. Wang, Q. Jiang, P. Li, C. Yu, R. Yuan, Z. Dong, T. Meng, F. Hu, J. Wang, H. Yuan, ACS Appl. Mater. Interfaces 2025, 17, 10986.[134] H. B. Overby, J. F. Ferguson, Curr. Hypertens. Rep. 2021, 23 .[135] L. Song, Y. Hou, D. Xu, X. Dai, J. Luo, Y. Liu, Z. Huang, M. Yang, J. Chen, Y. Hu, C. Chen, Y. Tang, Z. Rao, J. Ma, M. Zheng, K. Shi, C. Cai, M. Lu, R. Tang, X. Ma, C. Xie, Y. Luo, X. Li, Z. Huang, Cell Metab. 2025, 37, 104.[136] P. Li, Y. Zhang, H. Lang, P. Hou, Y. Yao, R. Zhang, X. Wang, Q. Zhang, M. Mi, L. Yi, Mol. Nutr. Food Res. 2025, 69, e202400491.[137] M. Sil, D. Mitra, N. Mukherjee, M. Gadani, A. Chatterjee, P. Sharma, A. Goswami, Indian J. Microbiol. 2025, 65, 765.[138] X. Guo, C. Li, J. Zhang, M. Sun, J. Xu, C. Xu, H. Kuang, L. Xu, Nat. Aging 2023, 3, 1415.[139] C. Qu, Q.P. Li, Z.R. Su, S.P. Ip, Q.J. Yuan, Y.L. Xie, Q.Q. Xu, W. Yang, Y.F. Huang, Y.F. Xian, Z.X. Lin, J. Adv. Res. 2022, 35, 231.[140] Y. Wu, Z. Tang, S. Du, J. Dai, J. Shen, H. Niu, X. Song, G. Huang, L. Du, Y. Jin, Int. J. Pharm. 2024, 658, 124225.[141] L. Li, H. Cui, T. Li, J. Qi, H. Chen, F. Gao, X. Tian, Y. Mu, R. He, S. Lv, F. Chu, B. Xu, P. Wang, H. Lei, H. Xu, C. Wang, Front. Pharmacol. 2020, 11, 1210.[142] X. Dong, P. Pan, D.W. Zheng, P. Bao, X. Zeng, X.Z. Zhang, Sci. Adv. 2020, 6, eaba1590.[143] D. Zheng, R. Li, J. An, T. Xie, Z. Han, R. Xu, Y. Fang, X. Zhang, Adv. Mater. 2020, 32, 2004529.[144] T. Lang, R. Zhu, X. Zhu, W. Yan, Y. Li, Y. Zhai, T. Wu, X. Huang, Q. Yin, Y. Li, Nat. Commun. 2023, 14, 4746.[145] Q. Liu, Y. Wu, Q. Fan, J. Liu, Y. Chen, Y. He, W. Wei, H. Zhang, Y. Zhao, Y. He, X. Du, J. Guo, ACS Nano 2025, 19(26), 23575.[146] Y. Luo, S. Peng, J. Cheng, H. Yang, L. Lin, G. Yang, Y. Jin, Q. Wang, Z. Wen, J. Funct. Biomater. 2024, 15, 236.[147] A. Sun, Q. Luo, H. Liu, W. Yang, J. Liu, X. Shi, Y. Nie, J. Sun, M. Sun, L. Liu, Nano Today 2025, 61, 102572.[148] W. Zhang, Y. Yuan, X. Li, J. Luo, Z. Zhou, L. Yu, G. Wang, Front. Immunol. 2022, 13, 900963.[149] Y. Zheng, Z. Zhang, Z. Fu, A. Fan, N. Song, Q. Wang, S. Fan, J. Xu, J. Xiang, X. Liu, ACS Nano 2024, DOI: 10.1021/acsnano.4c07332.[150] Q. Cheng, M. Xie, H. Ying, C. Jin, L. Yang, D. Ma, S. Cui, L. Shi, Chem. Eng. J. 2025, 505, 159706.[151] H. Choi, M.-J. Kwak, Y. Choi, A. N. Kang, D. Mun, J. Y. Eor, M. R. Park, S. Oh, Y. Kim, Gut Microbes 2025, 17, 2474256.[152] A. Mojadadi, A. Au, T. Ortiz Cerda, J. Y. Shao, T. O’Neil, K. Bell-Anderson, J. W. Andersen, J. Webb, W. Salah, G. Ahmad, H. H. Harris, P. K. Witting, Redox Rep. Commun. Free Radic. Res. 2025, 30 .[153] X. Wang, X. Cui, J. Wu, L. Bao, Z. Tan, C. Chen, Sci. Adv. 2023, 9, eadg2252.[154] C. Mac, H. Tai, S. Huang, H. Peng, A. K. Sharma, G. L. T. Nguyen, P. Chang, J. Wang, Y. Chang, Y. Lin, H. Sung, Adv. Mater. 2024, 36 .[155] B. Mangla, Y. R. Neupane, A. Singh, P. Kumar, S. Shafi, K. Kohli, Nanomed. 2020, 15, 2563.[156] S. Pushalkar, M. Hundeyin, D. Daley, C. P. Zambirinis, E. Kurz, A. Mishra, N. Mohan, B. Aykut, M. Usyk, L. E. Torres, G. Werba, K. Zhang, Y. Guo, Q. Li, N. Akkad, S. Lall, B. Wadowski, J. Gutierrez, J. A. Kochen Rossi, J. W. Herzog, B. Diskin, A. Torres-Hernandez, J. Leinwand, W. Wang, P. S. Taunk, S. Savadkar, M. Janal, A. Saxena, X. Li, D. Cohen, R. B. Sartor, D. Saxena, G. Miller, Cancer Discov. 2018, 8, 403.[157] Z.Y. Han, Q.W. Chen, Z.J. Fu, S.X. Cheng, X.Z. Zhang, Nano Lett. 2022, 22, 8608.[158] Y. Miao, K. Chen, C. Chen, F. Mi, Y. Lin, Y. Chang, C. Chiang, J. Wang, K. Lin, H. Sung, Adv. Mater. 2021, 33, 2100701. Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License.

Authors Metrics & Citations Metrics Article Usage 342views 192downloads Citations Download citation Jiaqi Ma, Yating Yang, Houbo Zhou, et al. Harnessing the Gut-X Axis: Novel Avenues for Oral Nanomedicine. Authorea. 26 October 2025. DOI: https://doi.org/10.22541/au.176150184.45661326/v1 DOI: https://doi.org/10.22541/au.176150184.45661326/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.