Engineering Nanomaterial Platform for Inflammatory Bowel Disease: Three-Dimensional Integration of Delivery Mechanism, Therapeutic Drug Delivery and Intelligent Material Design

Abstract

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder with a complex etiology and a high recurrence rate. Conventional treatments face significant limitations in targeting, stability, and efficacy. Going beyond conventional reviews that focus on isolated mechanisms, this review offers a systematic integration of three engineering perspectives: how to deliver (targeting mechanisms), what to deliver (pathology-based therapeutic payloads), and what to use for delivery (smart material design). We highlight emerging nanoplatforms—including nanozymes, probiotic-based nano-delivery systems, and stimuli-responsive nano-delivery systems—that address oxidative stress and gut dysbiosis, two core pathologies of IBD. We also discuss novel approaches for delivering nanodrugs to target cells and advocate for the use of hybrid synthetic/natural materials to achieve a balance between efficacy and safety of nanomaterials. However, a critical gap that must be confronted is that the vast majority of existing studies remain confined to acute, chemically induced colitis models (typically 7–14 days), which poorly recapitulate the chronic, relapsing nature of human IBD. Systematic validation of long-term safety and efficacy including biodistribution, metabolic clearance, and chronic toxicity profiles over extended periods is urgently needed before any meaningful clinical translation can be contemplated. This recognition of the acute-to-chronic translation gap constitutes a central critical stance of this review. This is not merely a methodological concern but a fundamental barrier that pervades the entire field: the disconnect between acute model readouts and chronic disease outcomes has systematically inflated translational expectations while masking the true challenges of long-term efficacy, safety, and durability. Addressing this gap requires not only acknowledging its existence but also implementing concrete, standardized protocols for chronic model evaluation. Multidisciplinary collaboration is urgently needed to accelerate clinical translation.

Introduction

Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions of the gastrointestinal tract, primarily comprising ulcerative colitis (UC) and Crohn’s disease (CD).¹ Its typical clinical manifestations include persistent abdominal pain, diarrhea, and hematochezia, severely impacting patients’ quality of life. Long-term recurrent episodes can lead to intestinal obstruction, fistulas, and even carcinogenesis.^2,3

Globally, IBD incidence varies markedly across regions, with annual rates of approximately 27 per 100,000 in Northern Europe, 20 per 100,000 in the United Kingdom, 19 per 100,000 in the United States, and 3 per 100,000 in Asia.⁴ The disease has emerged as a global public health challenge, with particularly high prevalence among young adults.^5–8 Despite substantial advances in understanding IBD pathophysiology, curative interventions remain lacking due to its complex etiology involving genetics, immunity, environment, and microbiota.⁹

UC and CD exhibit distinct anatomical distribution and inflammatory patterns that profoundly influence nanocarrier design. UC is confined to the colon and rectum, with continuous mucosal inflammation, making it amenable to topical or luminal delivery strategies. In contrast, CD can affect any gastrointestinal segment, with transmural, patchy inflammation (“skip lesions”) and a predilection for the terminal ileum. This necessitates nanocarriers capable of deeper tissue penetration and highlights the limitations of pH-responsive systems optimized solely for colonic delivery (pH≥7.0) in CD patients with ileal involvement (pH~6.0–7.5). Recognizing these differences is essential for disease-subtype-specific nanotherapies, yet most preclinical studies use generic colitis models that inadequately represent either condition.

Current IBD treatments include aminosalicylates, glucocorticoids, immunosuppressants, and biologic agents.^10,11 Recent advanced therapies—including vedolizumab (anti-α4β7 integrin), ustekinumab (anti-IL-12/23), tofacitinib (JAK inhibitor), and ozanimod (S1P receptor modulator)—have expanded the treatment landscape. However, reported clinical remission rates at one year remain modest (estimated 30–50% for biologics and 40–60% for JAK inhibitors), and many patients eventually lose response or experience intolerance. These suboptimal outcomes are largely attributed to poor tissue targeting, limited oral bioavailability, and the inability of single-pathway inhibitors to address the multifactorial pathogenesis of IBD—precisely the limitations that nanomedicines are designed to overcome through active targeting, localized delivery, and multi-agent co-delivery.^12–18

Oral administration is generally the most clinically desirable route for maintenance therapy in IBD and is strongly preferred by patients, as it enables direct topical exposure of therapeutic agents to the diseased intestinal mucosa while minimizing systemic exposure and associated side effects. This is especially relevant for UC, where pathology is confined to the colon. Oral formulations also offer better patient compliance and reduce treatment burden compared with parenteral routes—an important consideration given the chronic, relapsing nature of IBD, which often requires lifelong therapy. However, oral administration faces formidable biological barriers—gastric degradation, the epithelial barrier, and mucus clearance—which nanocarriers are specifically designed to overcome. Among gastrointestinal segments, the colon stands out as a particularly attractive target for oral nanocarriers, owing to its prolonged transit time (12–48 hours) and dense microbial ecosystem that enables enzyme-triggered release. Given that the majority of preclinical IBD models simulate colonic inflammation (UC), this review focuses primarily on colon-targeted strategies, while acknowledging that the findings are not directly generalizable to CD; CD-specific challenges are discussed separately in the Conclusion and Perspectives section.

In recent years, nanotechnology has opened new possibilities for IBD therapy.^19–22 Nanomaterials (1–1000 nm) offer advantages in drug stability, targeted accumulation, and integration of multiple therapeutic modules. Nanomedicine is uniquely positioned to address—namely, site-specific delivery to inflamed colonic tissue to reduce systemic immunosuppression; protection of biologics and nucleic acid payloads from gastrointestinal degradation and anti-drug antibody formation; extended residence time in the gut to sustain local drug concentrations; and the potential to re-establish mucosal tolerance, which current systemic agents do not directly achieve.²³ The evolution of IBD nanomedicine can be conceptualized in three phases: Phase I (2005–2010), early exploration with pH-responsive nanocarriers; Phase II (2015–2019), rapid development with active targeting and nanozyme technology; and Phase III (2020–present), diversified breakthrough with probiotic delivery systems, engineered live biotherapeutics, and synthetic–natural hybrid materials.^24,25 The 2011–2014 interval is intentionally not designated as a distinct phase because it represents a transitional zone with no new paradigm emergence, incremental advances, and continued low publication volume. This three-phase framework, while a heuristic for organizing the field’s conceptual evolution, should be understood as an analytical simplification rather than a precisely dated historical trajectory.

Effective colon-targeted delivery requires understanding gastrointestinal anatomical and microbial gradients. Anatomically, pH rises from stomach (1.0–3.5) to colon (6.0–7.5), transit time lengthens to 12–48 hours in the colon, and bacterial density increases dramatically to 10¹¹–10¹² CFU/mL in the colon. This dense microbial ecosystem provides opportunities for enzyme-triggered drug release via azoreductase and polysaccharide-degrading enzymes. However, these barrier properties are not static—in active IBD, they are significantly altered—colonic luminal pH can drop to 2.3–5.5 during acute flares, rendering traditional pH-responsive coatings (Eudragit® S100, dissolution threshold ≥7.0) unreliable. Inflammation also disrupts the mucus layer and epithelial tight junctions, though the latter remains insufficient for efficient nanoparticle traversal.

In contrast to earlier reviews that often emphasize isolated mechanisms or individual strategies, the present review establishes a three-dimensional integrated framework that spans how to deliver (targeting mechanisms), what to deliver (pathology-based therapeutic payloads), and what to use for delivery (smart material design). Given that most preclinical models focus on colonic inflammation (UC), we prioritize colon-targeted delivery and provide critical analyses of mechanistic principles, cross-platform comparisons, and translational barriers.²⁶

To date, no nanomedicine has received specific FDA approval for IBD, and the existing regulatory pathways are complex and not tailored to nanomedicines; key clinical milestones, including liposomal budesonide (Phase II), nanocapsulated cyclosporine A (early stage), and siRNA nanoparticles (preclinical); the failure of several promising candidates that succeeded in acute models to advance to clinical use, highlighting the animal-to-human translation gap; specific regulatory and practical obstacles, such as batch consistency, GMP manufacturing costs, and the lack of validated biomarkers; and the need to address these challenges in parallel with scientific development. This background clarifies why—despite abundant preclinical innovation—clinical translation remains limited.

Colon-Targeted Nanodelivery Strategy

The low targeting efficiency of traditional oral drugs is a major factor limiting their therapeutic efficacy in IBD.^27,28 Nanocarriers—constructed by leveraging the microenvironmental characteristics of inflammatory lesions (passive targeting) and specific molecule–mediated recognition strategies (active targeting)—enable precise drug delivery and accumulation at the lesion site, thereby improving therapeutic efficacy and reducing systemic side effects.

Passive Colon-Targeted Nanodelivery Strategy

The pH value of the colon (6.5–7.5) is higher than that of the stomach and small intestine. The characteristics of elevated colonic pH, abnormal activation of certain enzymes at the lesion site, and increased oxidative stress enable the design of signal-responsive nanocarriers for intelligent and controlled drug release at inflammatory lesions.^29,30 To date, pH-sensitive polymers (such as sodium alginate, chitosan derivatives, and the Methacrylic Acid Copolymer) are widely used to construct colon-targeted delivery systems.^31–34 For example, chitosan derivatives remain stable at acidic pH (< 6.0) but swell and release drugs in the neutral to weakly alkaline environment of the proximal colon (pH 6.0–6.5), offering advantages for cecal or ascending colon delivery.³⁵ Methacrylic Acid Copolymer, Type A dissolves at pH ≥ 6.0 and is more appropriate for the proximal colon or small intestinal targeting.^36,37 The sodium alginate hydrogel nanoemulsion loaded with curcumin/daucosterin (Cur/Emo NE@SA) maintains structural stability under gastric acid conditions, whereas under colonic pH conditions, the gel swells and releases the drugs, enhancing the colonic bioavailability of curcumin and significantly alleviating colitis symptoms in mice.³⁸ PEG-modified PLGA nanoparticles loaded with cyclosporine A form a protective layer on their surface due to PEG, which resists gastric acid (pH 1.2) but is shed only under colonic pH conditions. This enhances degradation of the PLGA core and facilitates drug release, resulting in a fourfold higher drug concentration in the colonic region compared to PEG-free PLGA carriers. Aib et al³⁹ designed pH-sensitive liposomes coated with Methacrylic Acid Copolymer, Type B for the co-delivery of mesalazine (MZ) and curcumin (CM) in the colon, aiming to achieve synergistic therapy for ulcerative colitis (UC). MZ is a hydrophilic 5-aminosalicylic acid derivative encapsulated within the liposomal aqueous core; CM is a hydrophobic natural polyphenol embedded in the lipid bilayer. The Methacrylic Acid Copolymer, Type B coating on the liposome surface is a pH-sensitive polymer that remains intact under the acidic gastric environment (pH 1.2); upon reaching the colon (pH ≥ 7), the coating dissolves, exposing the liposomes and releasing both drugs (Figure 1). However, a critical caveat is that active IBD patients often exhibit reduced colonic pH (ranging from 2.3 to 5.5 in severe cases) due to inflammation-associated organic acid accumulation and diarrhea.⁴⁰ Under such acidic conditions, traditional pH-responsive coatings with dissolution thresholds above pH 7.0 are likely to fail, highlighting the need for low-pH-responsive or pH-independent strategies. Although pH-responsive polymers represent the most extensively developed colon-targeting strategy, their fundamental premise—that colonic pH is consistently neutral to weakly alkaline—is pathophysiologically invalid in active IBD. Clinical measurements have documented that colonic luminal pH in severe IBD can drop to 2.3–5.5 due to organic acid accumulation from bacterial fermentation, epithelial metabolic dysfunction, and diarrhea-induced rapid transit. This means that a pH-responsive coating designed to dissolve at ≥7.0—the threshold for Methacrylic Acid Copolymer, Type B—will either remain intact or dissolve prematurely and unpredictably depending on the heterogeneous pH landscape of the inflamed colon.

Figure 1.

Utilizing the gastrointestinal pH gradient (from stomach to colon), co-delivering hydrophilic mesalazine (in the aqueous core) and hydrophobic curcumin (in the lipid bilayer) via Methacrylic Acid Copolymer, Type B-coated liposomes, triggered by colonic pH (≥ 7.0) to dissolve the coating and release the drug at the inflammatory site. The arrows indicate the final delivery path of lipid-based preparations through the gastrointestinal tract (stomach → small intestine → colon → rectum), including the degradation of the membrane and the release of the drug in the colonic pH environment. Created with BioGDP.com.⁴¹

More concerning is that the spatial heterogeneity of pH within the same IBD patient—with some regions acidic and others near-neutral—renders single-threshold systems inherently unreliable. Furthermore, pH-responsive systems offer no mechanism to distinguish between healthy and inflamed mucosa beyond pH, meaning that drug release occurs throughout the colon wherever the threshold is met, rather than specifically at inflammatory lesions. This fundamental mismatch between design assumptions and clinical reality raises a critical question: should the field continue investing in pH-responsive systems for IBD, or pivot toward multi-responsive and pH-independent strategies that can operate reliably across the full spectrum of disease conditions? Some recent reviews have similarly called for a transition beyond single-mechanism responsiveness toward integrated multi-responsive platforms that combine pH sensitivity with ROS- or enzyme-triggered release. It is important to qualify this criticism, as the failure concerns single-threshold pH-responsive release systems that rely entirely on a specific colonic pH value to trigger drug release. This stands in marked contrast to the use of pH-responsive polymers as protective enteric coatings in hierarchical multi-responsive platforms, where pH sensitivity serves only to prevent gastric degradation, while drug release is actually triggered by local inflammatory signals—such as elevated ROS or specific enzymes—at the disease site. In such contexts, the pH-responsive material functions as a simple binary protective barrier (intact at low pH, dissolving at higher pH) rather than as a precision delivery trigger that relies on a narrow pH threshold. This conceptual distinction is further developed in the hierarchical platform proposal presented in the Conclusions and Perspectives section. Moreover, the choice of the pH-responsive coating can be tailored to the target disease location: Methacrylic Acid Copolymer, Type A (dissolution at ≥ pH 6.0) for ileal Crohn’s disease, and Methacrylic Acid Copolymer, Type B (dissolution at ≥ pH 7.0) for colonic ulcerative colitis. The colonic symbiotic microbiota expresses enzymes such as azoreductase and polysaccharide-degrading enzymes, whereas inflammation-associated proteases (eg, matrix metalloproteinases, trypsin) are highly expressed at the inflamed site. This enables the construction of enzyme-based delivery systems. For example, azo-based nanocarriers are specifically cleaved by azoreductase produced by colonic commensal bacteria, enabling localized drug release.⁴² Chen et al developed microencapsulated nanogels loaded with TNF-α siRNA based on an enzyme–pH dual-responsive strategy. The framework was constructed using polymethylacrylate-co-N-vinyl-2-pyrrolidone (P(MAA-co-NVP)), with microcapsules formed through a trypsin-degradable peptide crosslinker that encapsulated the TNF-α siRNA-containing nanogels. Under the acidic gastric environment (pH 2–4), the P(MAA-co-NVP) backbone collapses to form a protective barrier that prevents siRNA degradation. Upon reaching the intestinal environment (pH 6.5–7.5), the backbone swells, allowing enzymes such as trypsin to degrade the peptide crosslinking agent, thereby releasing the nanogel to facilitate cellular uptake. The released TNF-α siRNA nanogel effectively reduced secretory TNF-α levels in mouse macrophages.⁴³ While enzyme-responsive systems offer the advantage of adaptive release (eg, slower release in severe dysbiosis), this microbial dependence paradoxically introduces interpatient variability, posing challenges for predictable dosing.

In IBD, reactive oxygen species (ROS) levels are abnormally elevated at the inflammatory sites. ROS-responsive carriers—typically containing aryl borates, thioketals, or diselenide bonds—undergo cleavage under the high ROS conditions (eg, H₂O₂ concentrations > 100 μM) characteristic of inflamed intestinal mucosa,⁴⁴ thereby enabling on-demand drug release. The Janus prodrug nanoparticles (B-ATK-T NPs) link budesonide and the antioxidant Tempol via an aryl thioacetone (ATK) bridge. In a high ROS environment, ATK rapidly cleaves to release the drug, significantly increasing the drug concentration at the inflamed site of the colon.⁴⁵ Similarly, ROS-responsive polyether micelles were used to encapsulate budesonide; upon exposure to H₂O₂, the sulfide bonds break, leading to micelle dissociation and release of budesonide. After intervention with this system, the remission rate of colitis in mice was significantly superior to that achieved with budesonide alone.⁴⁶

Each of the three passive colon-targeted nanodelivery strategies presents unique benefits and drawbacks, and the pH-responsive approach stands out as the most extensively developed and validated.

Active Colon-Targeted Nanodelivery Strategy

Unlike passive delivery strategies targeting the physicochemical characteristics of the intestinal microenvironment, active strategies primarily involve surface modification of nanocarriers with ligand molecules. These ligands can specifically recognize and bind to receptors that are overexpressed at inflammatory sites or on the surfaces of specific immune cells. Through the specific binding of ligands to receptors, the carriers are actively directed to the site of intestinal inflammation and selectively internalized by target cells.^47,48 Based on the type of target cells and their role in IBD pathology, active targeting strategies can be classified into the following three categories.

CD44-Mediated Drug Delivery to Inflamed Intestinal Cells

In IBD, the expression of CD44 on the surfaces of intestinal epithelial cells, activated fibroblasts, and infiltrating immune cells (such as macrophages and T cells) is significantly enhanced.^49,50 Hyaluronic acid (HA) is a natural glycosaminoglycan that acts as the primary ligand for CD44 and possesses excellent biocompatibility, biodegradability, and anti-inflammatory properties. Through surface HA chains, HA-modified nanoparticles (HANPs) specifically bind to CD44 on cellular membranes in the inflamed colonic tissue, leading to endocytosis and subsequent intracellular drug delivery.⁵¹

The study by Huai et al⁵² demonstrates that, in a colitis mouse model, the HANPs-treated group loaded with anti-inflammatory drugs exhibited significantly reduced inflammatory scores in the colonic mucosa, markedly decreased expression levels of pro-inflammatory factors (eg, TNF-α, IL-1β), and restored expression of proteins related to intestinal epithelial barrier function (eg, occludin, ZO-1) (Figure 2). Of note, endogenous HA released by fibroblasts in the inflamed colonic tissue accumulates abundantly at the inflammatory site, occupying CD44 receptor binding sites and thereby reducing the targeting efficacy of exogenous HA.

Figure 2.

(a) Synthesis of HASe-Cr nanogel via amide bond formation in a mild EDC/NHS system. (b) Therapeutic mechanisms of the nanogel in IBD treatment. The nanogel achieves high targeting of inflamed tissues through a dual strategy (electrostatic adsorption and HA-CD44 binding), and subsequently ameliorates colitis by restoring mitochondrial energy metabolism, suppressing pro-inflammatory cytokine secretion, promoting M2 macrophage polarization, repairing the epithelial barrier, and modulating the gut microbiota. In the bottom-left panel of (b), the red upward arrow denotes beneficial effects, including upregulation of tight junction proteins (ZO-1, OCLN, CLDN) and anti-inflammatory cytokine IL-10; the red downward arrow indicates significant downregulation of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6). In the top-left panel of (b), the blue upward arrow signifies elevated reactive oxygen species (ROS), which contribute to gut dysbiosis, while the red downward arrow represents reduced ROS after nanogel treatment. HA, hyaluronic acid (CD44 ligand); Se, selenium (antioxidant); Cr, creatine (mitochondrial recovery). Reproduced with permission from Ref.52 2024, Springer Nature.

CD206-Mediated Drug Delivery to Immune Cells

The imbalance between pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages plays a central role in the progression of IBD.⁵³ Reshaping the phenotype and function of macrophages has become an effective approach to modulate the pathological progression of IBD.⁵⁴ The mannose receptor (CD206) is highly expressed on the surface of M2 macrophages.⁵⁵ Mannose-modified nanoparticles, through the ligand–receptor interaction between mannose and CD206, can be directed toward M2 macrophages and promote macrophage polarization toward the M2 phenotype.^56,57 Zhu et al utilized selenium, which possesses antioxidant and anti-inflammatory properties, to develop mannose-coated selenium nanoparticles (M-SeNPs).⁵⁸ After mannose modification, the uptake efficiency of M-SeNPs by macrophages was significantly enhanced. In vivo experiments demonstrated that M-SeNPs promote macrophage polarization from the M1 to the M2 phenotype in colonic tissue, thereby significantly alleviating enteritis and facilitating intestinal tissue healing. This dual mechanism of “targeted delivery combined with coordinated regulation of innate immunity” helps control the progression of IBD by modulating the immune microenvironment.

Integrin-Mediated Drug Delivery to Vascular Endothelial Cells

The integrin αvβ3 is highly expressed on the surface of neovascular endothelial cells in the inflamed sites of IBD.⁵⁹ The cRGD (cyclic Arg-Gly-Asp) peptide exhibits high specificity and strong binding affinity for integrin αvβ3.⁶⁰ Qi et al⁶¹ modified polybutylcyanoacrylate microbubbles with cRGD and found that the binding signal of cRGD microbubbles at the inflamed sites of colitis mice was significantly enhanced; the binding signal was positively correlated with the expression level of integrin αvβ3 (r = 0.8, P = 0.0016). Du et al⁶² loaded the anti-inflammatory drug patchouli alcohol into cRGD-functionalized silk fibroin nanoparticles. Upon oral administration, this nanosystem enhanced nanoparticle accumulation at inflamed colonic sites and, as a consequence, markedly alleviated colonic inflammation while restoring intestinal barrier integrity in colitis mice.

MAdCAM-1 (mucosal addressin cell adhesion molecule-1) is highly expressed on the vascular endothelial cells of the inflamed colon.⁶³ MAdCAM-1 is a ligand for the α4β7 integrin (which is highly expressed on the surface of white blood cells that home to the intestine in IBD patients). Truffi et al⁶⁴ constructed PLGA–PEG nanoparticles conjugated with anti-MAdCAM-1 antibody fragments and used them for tissue imaging by loading quantum dots. In the chronic IBD mouse model, 24 hours after injection of anti-MAdCAM-1 antibody fragment–conjugated PLGA–PEG nanoparticles, the accumulation of quantum dots in the intestine was significantly higher than that of the non-conjugated PLGA–PEG nanoparticles.

Furthermore, Diefenbach et al⁶⁵ utilized the MAdCAM-1 D1D2 domain fusion protein to construct lipid nanoparticles that specifically bind to the α4β7 integrin on leukocytes and deliver IFN-γ siRNA. Thereby, the IFN-γ gene in intestinal homing leukocytes in the colitis model is selectively silenced, and colitis symptoms are improved. Beyond ligand–receptor mediated targeting, emerging “intelligent nanodevice” platforms offer new paradigms for active delivery with precise molecular control.

The “lock-and-key” type recognition mechanism of ligand–receptor interactions confers extremely high spatial resolution and cell-targeting ability to nanomedicines, which is conducive to overcoming the off-target effects of traditional drugs and is considered one of the core strategies for achieving precise immunological intervention in IBD (Figure 3).

Figure 3.

Schematic representation of three major active targeting mechanisms: CD44-mediated delivery to inflamed intestinal epithelial cells, CD206-mediated delivery to M2 macrophages, and integrin αvβ3-mediated delivery to vascular endothelial cells. Created with BioGDP.com.⁴¹

The above four active targeting strategies (CD44-mediated, CD206-mediated, integrin αvβ3-mediated, and MAdCAM-1-mediated) exhibit distinct ligand-receptor pairs, cellular targets, and inherent limitations, which are summarized and compared in Table 1.

Table 1.

Comparative Analysis of Active Targeting Strategies for Colon

Mechanisms of Targeted Delivery	Target Cells	Receptor	Ligands	Ligand Selection Rationale	Potential Limitations
CD44 mediated mechanism	Inflamed epithelial cells, activated fibroblasts, and infiltrating immune cells	CD44	Hyaluronic acid (HA)	CD44 is widely expressed in inflamed sites. HA has anti-inflammatory activity	Endogenous HA in inflamed colon competitively blocks exogenous HA binding, reducing targeting efficacy.
CD206-mediated mechanism	M2 macrophages	CD206	Mannose	CD206 is highly expressed on M2 macrophages; this delivery strategy can promote M1→M2 polarization	Targets immune cells but does not directly repair damaged intestinal epithelial barrier.
Integrin αvβ3 mediated mechanism	Neovascular endothelial cells	Integrin αvβ3	cRGD peptide	Targeting angiogenesis to block the supply of inflammatory nutrients; Inhibition of pathological vascular remodeling	αvβ3 is also expressed in normal neovascularization (eg, wound healing), posing off-target risk.
MAdCAM-1 mediated mechanism	Gut-homing leukocytes	MAdCAM-1	Anti-MAdCAM-1 antibody	MAdCAM-1 is highly expressed on the vascular endothelial cells of the inflamed colon; the therapeutic effect of anti-madCAM-1 antibody is clinically validated.	Effectiveness depends on MAdCAM-1 upregulation during active IBD; higher cost and potential immunogenicity.

Strategies for Nanoparticles to Break Through the Mucosal Barrier

The barriers that nanoparticles encounter after oral administration are not universal—they depend on the intended therapeutic destination. This section organizes the barrier discussion according to the design goal of the nanocarrier. For platforms designed for luminal or mucosal surface delivery, the primary consideration is overcoming the mucus layer and, in some cases, achieving epithelial adhesion without crossing into the lamina propria. For platforms designed for epithelial or subepithelial targeting, mucus penetration and epithelial crossing become necessary. For platforms designed for targeting of lamina propria immune cells or systemic delivery, the additional challenge of mononuclear phagocyte system (MPS) -mediated clearance must be addressed.

To reach their intended therapeutic targets in the colon, nanoparticles must overcome a series of barriers, but the specific barriers encountered depend on the therapeutic goal. This review identifies a three-tiered barrier framework: for nanocarriers designed for luminal or mucosal surface delivery—such as topical anti-inflammatory agents (eg, 5-ASA, budesonide), probiotic formulations, or mucus-adhesive systems—the primary barriers are the mucus layer (which may trap carriers and lead to clearance via mucus turnover) and the epithelial barrier (which must be circumvented only if the carrier requires epithelial access; for purely luminal systems, this barrier is intentionally avoided). MPS clearance is not a relevant barrier for these platforms, as they are designed to remain in the intestinal lumen or mucosa and do not enter the circulation. For nanocarriers designed to reach targets beyond the epithelium—such as those targeting lamina propria macrophages, agents intended for transmural delivery in Crohn’s disease, or drugs delivering biologics requiring systemic absorption—the barriers are the mucus layer, the epithelial barrier (which must be crossed via transcellular or paracellular routes), and the immune cell clearance (MPS) barrier in the lamina propria or circulation. In practice, the three barriers differ in their scope. Mucus is universally encountered; the epithelium only becomes relevant when epithelial crossing is intended. MPS clearance—whether by immune cells in the lamina propria or in the circulation—comes into play as soon as the platform reaches the lamina propria, since local phagocytes at this site already present a clearance risk, irrespective of eventual systemic exposure.

Approaches to Enhancing Nanoparticle Penetration Through the Mucus Layer

A critical distinction must be made between mucus penetration and mucus adhesion, as these two strategies serve fundamentally different therapeutic purposes. The surface of the intestinal epithelium is covered by a mucus gel composed of mucin, with a pore size of approximately 10–200 nm. Traditional nanoparticles are easily captured by mucin through hydrophobic or electrostatic interactions, resulting in clearance before reaching the epithelium.

Mucus penetration is achieved through surface modifications such as PEGylation, which creates a hydrophilic “cloud” that reduces hydrophobic and electrostatic interactions with mucin fibers, enabling nanoparticles to diffuse through the mucus mesh and reach the epithelial surface. This approach is appropriate when the therapeutic target lies beyond the epithelium—such as for drugs requiring systemic absorption, active targeting to lamina propria immune cells (eg, macrophages), or delivery to deeper tissue layers in transmural CD. Sato et al⁶⁶ developed PEG–PLGA nanoparticles (CsA/MNP) and found that their penetration in artificial mucus was three times higher than that of conventional PLGA nanoparticles. Reducing the size of nanoparticles also helps overcome the mucus barrier. Zhao et al⁶⁷ prepared ultra-small amphoteric ion nanoparticles (HC-CB NPs, <10 nm) that can effectively penetrate the mucus layer and cross the epithelial barrier via the PAT1 (proton-coupled amino acid transporter 1) pathway.

Mucus adhesion, by contrast, is achieved using polycationic materials such as chitosan, whose positive charge interacts electrostatically with negatively charged mucin sialic acid residues. This enhances carrier retention within the mucus layer and prolongs intestinal residence time, making it suitable for topical drug delivery (eg, 5-ASA, budesonide) where mucosal surface exposure is sufficient, or for probiotic colonization where microbiota modulation is the therapeutic goal. The critical trade-off is that strong mucus adhesion can also trap carriers in the outer mucus layer, preventing epithelial access and leading to rapid clearance via mucus turnover. Thus, the choice between penetration and adhesion must be guided by the therapeutic goal and disease subtype: superficial UC may benefit from adhesion strategies, whereas transmural CD may require penetration to reach deeper tissue layers.

An alternative approach is to temporarily disrupt the mucus layer itself, for example by loading a mucus-dissolving agent such as N-acetylcysteine onto the nanoparticle surface.⁶⁸ Emerging hierarchical designs, such as “adhesion-then-penetration” systems with mucoadhesive outer coatings that degrade to reveal penetrative surfaces, offer the advantages of both strategies while mitigating their individual limitations. The NE layer in the HPN-NE-EcN system exemplifies this concept: it initially confers strong mucoadhesion for prolonged retention, then the system’s subsequent shedding enables deeper tissue interaction.

Approach to Facilitating Nanoparticle Passage Through the Intestinal Epithelial Physical Barrier via Endocytosis and Exocytosis

After passing through the mucus layer, nanoparticles still need to cross the selective barrier composed of tightly connected intestinal epithelial cells before reaching the lamina propria. In IBD conditions, the expression of tight junction proteins (eg, occludin, ZO-1) is downregulated, and epithelial permeability increases; however, this increase is still insufficient for most nanoparticles to traverse efficiently. So far, several translocation strategies have been developed. For example, HC-CB NPs can be internalized by intestinal epithelial cells via the proton-coupled amino acid transporter PAT1 and subsequently exocytosed from the basolateral side, thereby crossing the epithelial layer via transcellular transport. Microfold cells (M cells) are specialized epithelial cells responsible for antigen sampling and highly express receptors such as CLEC4G on their apical surface. Certain ligands can bind specifically to these receptors, mediating nanoparticle uptake and trans-epithelial transport across M cells.^69,70

Approaches to Controlling the Nanoparticles Clearance by Immune Cells

For nanocarriers designed to cross the epithelium and enter the lamina propria or circulation, a third barrier- MPS clearance-is encountered. It is important to emphasize that for nanocarriers designed to remain in the intestinal lumen or at the mucosal surface for local drug release or probiotic colonization, MPS clearance does not apply.⁷¹

For those platforms that do require systemic access, several strategies can be employed to inhibit phagocytosis and clearance by immune cells. For instance, modifying the nanoparticles surface with CD47 or its mimetic peptides enables binding to the SIRPα receptor on macrophages and transmits inhibitory signals, thereby avoiding phagocytosis through signal modulation.⁷² Encapsulating nanoparticles with biomimetic membranes—such as red blood cell membranes, white blood cell membranes, or platelet membranes—disguises them as “self-components” to evade immune recognition. Optimizing nanoparticle size and shape also helps avoid immune clearance: ultra-small size (<10 nm) reduces MPS recognition, and compared with spherical particles, disc-shaped or filamentous nanoparticles are less readily recognized by the MPS and thus exhibit longer retention times in the lamina propria or circulation.

Nanotherapeutic Strategies Based on the Pathogenesis of IBD

The pathological process of IBD involves multiple aspects such as oxidative stress escalation, abnormal activation of immune cells, and disruption of the intestinal microbiota. Traditional drugs suffer from a single mechanism of action, poor targeting, and low stability in the digestive tract, resulting in limited efficacy. Based on the pathological mechanisms, three nanotherapeutic strategies for IBD have been developed: nanozymes for regulating oxidative stress, probiotic nanodelivery systems, and nanoplatforms based on natural products. This forms a paradigm for constructing nanodelivery systems based on the pathogenesis.

Nanozymes for Regulating Oxidative Stress

Oxidative stress is a key driver of IBD pathogenesis. Under inflammatory conditions, elevated ROS levels attack intestinal epithelial membranes, disrupt mucosal barrier integrity, and exacerbate inflammatory cascades,^73,74 Therefore, effectively eliminating ROS and restoring redox balance represent a key therapeutic strategy.⁷⁵ Traditional antioxidants (eg, N-acetylcysteine, superoxide dismutase) suffer from poor stability, short half-lives, and insufficient targeting.⁷⁶

In recent years, nanozymes—nanomaterials with enzyme-like catalytic activity—have emerged as a versatile platform for antioxidant therapy in IBD. While some nanozymes (mainly metal-based nanoenzymes) operate through the SOD-to-CAT cascade, others (such as organic/polymer-based nanozymes) employ distinct mechanisms, including GPx-like activity (reducing peroxides using glutathione), NADH oxidase-like activity (converting NADH to NAD⁺), and Nrf2/HO-1 pathway activation (upregulating endogenous antioxidant defenses). Some also exhibit peroxidase-like activity, which can generate •OH radicals. This mechanistic diversity reflects the broad chemical composition of nanozymes, and different classes are better characterized by distinct catalytic pathways. Based on their composition and structural characteristics, existing nanozymes can be classified into four categories: inorganic nanozymes, Prussian blue and its analogues, organic/polymer-based nanozymes, and MOF-based nanozymes (Figure 4). While each class operates on the common principle of redox cycling to scavenge ROS, their distinct physicochemical properties lead to different advantages, limitations, and translational readiness. Below, we dissect each class before synthesizing a cross-category comparison.

Figure 4.

Cascade catalytic mechanism and representative nanozymes for ROS scavenging. The nanozyme with superoxide dismutase (SOD)-mimetic activity converts superoxide anion (•O₂⁻) to hydrogen peroxide (H₂O₂), which is subsequently decomposed into H₂O and O₂ by the catalase (CAT)-mimetic nanozyme. Representative nanozymes include metal-based nanozymes with multivalent redox cycling (eg, Mn₃O₄, Mo₃Se₄, Ni₃S₄), Prussian blue analogues with enhanced or multifunctional catalytic activity (eg, ultra-small Prussian blue nanoparticles, manganese-doped Prussian blue, selenium-loaded Prussian blue), organic/polymer-based nanozymes (eg, selenium nanogels), and metal–organic framework (MOF)-based nanozymes. In the bottom-right panel, the red and blue upward arrows indicate elevated levels of pro-inflammatory and anti-inflammatory cytokines, respectively; the red downward arrow indicates reduced pro-inflammatory cytokine expression; the black downward arrows indicate downregulation of intestinal barrier proteins (Claudin-1, Occludin, ZO-1); the central dashed arrow represents ROS conversion to H₂O and O₂; and the right dashed arrow indicates M1-to-M2 macrophage polarization. Created with BioGDP.com.⁴¹

Inorganic Nanozymes (Excluding Prussian Blue)

Inorganic nanozymes (mainly single- or dual-metal nanoparticles) rely on variable-valence metal ions (eg, Mn²⁺/Mn³⁺, Mo⁴⁺/Mo⁵⁺/Mo⁶⁺, Se²⁻/Se⁰) to mimic SOD and CAT in cascade. Their core advantages are high catalytic efficiency and a relatively simple synthesis process. For instance, Zhang et al⁷⁷ designed Mn₃O₄ nanoparticles with a diameter of approximately 50 nm, which facilitates their penetration through the intestinal mucus layer and delivery to the inflamed epithelium. In a DSS-induced colitis mouse model, oral administration of Mn₃O₄ led to specific accumulation at colonic inflammatory sites. The redox cycling between surface Mn²⁺/Mn³⁺ enabled these nanoparticles to simultaneously mimic the activities of superoxide dismutase and catalase, establishing a cascading ROS clearance pathway: first, via superoxide dismutase-like activity, the more toxic superoxide anion was converted into hydrogen peroxide; then, via catalase-like activity, hydrogen peroxide was further catalytically decomposed into harmless water and oxygen—thereby avoiding accumulation of intermediate products and associated tissue damage. Guo et al⁷⁸ prepared Mo₃Se₄ nanoparticles, which—through multivalent redox cycling of Mo⁴⁺/Mo⁵⁺/Mo⁶⁺ and Se²⁻/Se⁰—also achieved this cascading ROS clearance effect; their surface cross-linked structure conferred excellent gastrointestinal stability. Additionally, Chen et al⁷⁹ synthesized RuCo bimetallic nanosheets, which—owing to their unique two-dimensional sheet structure—simultaneously scavenge ROS and suppress pro-inflammatory cytokines; the sheet morphology also enhanced gastric acid stability, enabling successful delivery to the colon (Figure 5a). Zou et al⁸⁰ constructed nanozymes via self-assembly of zinc ions (Zn²⁺) with organic ligands, integrating chitosan and hyaluronic acid; these nanozymes concurrently enhanced ROS and hydrogen sulfide (H₂S) scavenging while improving adhesion to inflamed tissues (Figure 5b). In vivo experiments demonstrated that they significantly upregulated the expression of tight junction proteins such as ZO-1 and occludin.⁸¹ These simple inorganic nanozymes offer high catalytic efficiency and straightforward synthesis; however, long-term metal ion retention and potential chronic toxicity remain inadequately investigated. Their in vivo behavior is highly dependent on size and surface properties, yet systematic optimization of these parameters in chronic colitis models is still lacking. Table 2 summarizes the characteristics, therapeutic effects, and mechanisms of action of several metal-based nanozymes.

Figure 5.

(a) Synergistic SOD–CAT catalytic process of the RuCo nanozyme and its antioxidative therapeutic mechanism. RuCo, ruthenium–cobalt bimetallic nanosheets; SOD, superoxide dismutase; CAT, catalase. The downward arrows of various colors indicate the decrease in pro-inflammatory factors (IL-1β, TNF-α, IL-6) and reactive oxygen species (ROS) after antioxidant treatment. Reproduced with permission from.⁸⁰ 2025, American Chemical Society. (b) Construction of a pH-responsive metal–organic coordination complex, S-Z@CS/HA, and its therapeutic mechanism for colitis. In panel (b), the green upward arrows indicate promotion of protective factors (tight junction proteins ZO-1/Occludin, mucus layer, probiotics, M2 macrophage polarization, and TGF-β), while the red downward arrows indicate suppression of detrimental factors (pathogenic bacteria, LCN-2, MPO, COX-2, iNOS, and pro-inflammatory cytokines TNF-α, IFN-γ, IL-6). Together, they reflect the dual mechanism of nanotherapy in both suppressing inflammation and promoting tissue repair. Reproduced with permission from Ref.81 2025, Elsevier Ltd.

Table 2.

Characteristics, Therapeutic Effects, and Proposed Mechanisms of Metal-Based Nanozymes in IBD Models

Types of Nanozymes	Core Metal Ion Valence Cycling	Functional Mechanism	Gastrointestinal Stability Design	Treatment Effect	Ref
Mn3O4 nanozyme	Mn2⁺/Mn3⁺	ROS scavenging; intestinal barrier repair; microbiota regulation	Not mentioned	Significantly reduces inflammation score in colitis mice	[78]
Mo3Se4 nanozyme	Mo4⁺/Mo5⁺/Mo6⁺, Se2−/Se0	Full-spectrum ROS scavenging; enhanced adhesion to inflamed intestinal epithelial cells	Surface Se-Mo crosslinked structure; resistant to pH 1.0–3.0 gastric acid and pepsin	Alleviates inflammation through synergistic regulation of oxidative stress, intestinal barrier repair, and microbiota balance; without metal accumulation risk	[79]
RuCo bimetallic nanosheets	Not specified	Cascade catalytic ROS scavenging; reduction of pro-inflammatory cytokines	Sheet-like structure improves gastric stability	Successfully colonizes the colon; significantly reduces pro-inflammatory cytokine levels	[80]
Zinc-coordination-driven nanozyme	Zinc ion valence cycling	ROS/H2S scavenging; enhanced adhesion	Chitosan-hyaluronic acid-based nanoplatform	Reduces colitis score; upregulates tight junction proteins ZO-1 and Occludin	[81]
Ni3S4 nanozyme	Ni2⁺/Ni3⁺/Ni4⁺	Dual-enzyme cascade ROS scavenging; microbiota regulation	Resists pH 1.2 gastric acid and digestive enzymes	Specifically enriches in inflamed colonic regions; reshapes gut microbiota balance	[82]

Prussian Blue Nanozyme

Prussian blue and its analogues achieve efficient scavenging of ROS through an open-framework structure and tunable metal centers. For instance, the zero-valent selenium-enriched Prussian blue nanozyme developed by Zhu et al⁸² uses Prussian blue as the framework and promotes ROS scavenging via the Fe²⁺/Fe³⁺ redox cycle; the zero-valent selenium loaded onto it acts as an activator of glutathione peroxidase 4 (GPX4), thereby inhibiting cellular ferroptosis. In a DSS-induced colitis mouse model, this nanozyme protects intestinal epithelial cells through both “ROS scavenging and ferroptosis inhibition” pathways. In vivo experiments also showed that it reduces the proportion of pro-inflammatory Th17 cells, demonstrating potential for intervention in the multifaceted pathological processes of IBD. Yang et al⁸³ designed ultra-small Prussian blue nanodots with a particle size of less than 5 nm. Owing to a significant increase in specific surface area and greater exposure of catalytically active sites, they exhibit substantially higher catalase (CAT)-like activity, as evidenced by the efficient decomposition of H₂O₂ into H₂O and O₂, compared with conventionally sized Prussian blue particles. This CAT-like activity is mechanistically distinct from peroxidase (POD)-like activity, which requires an additional electron donor substrate for the reduction of H₂O₂. In the colitis model, they display superior anti-inflammatory effects (Figure 6a). Luo et al⁸⁴ designed tungsten-doped Prussian blue nanoparticles by incorporating tungsten into the classic Prussian blue lattice structure, thereby enhancing the ROS-scavenging capacity of the nanoparticles and alleviating colitis (Figure 6b). Similarly, Zhao et al⁸⁵ constructed manganese-doped Prussian blue nanozymes, in which the Prussian blue framework provides superoxide dismutase-like activity to convert superoxide anions into hydrogen peroxide, while manganese confers catalase (CAT)-like activity to decompose hydrogen peroxide into water and oxygen through dismutation (2H₂O₂ → 2H₂O + O₂). This is mechanistically distinct from peroxidase (POD)-like activity, which requires an additional electron donor substrate (eg, TMB or ABTS) and does not produce molecular oxygen as a primary product. After oral administration, this nanozyme resists degradation by gastric juice and achieves targeted enrichment in the inflamed colon without impairing hepatic or renal function. Table 3 summarizes the performance characteristics, anti-IBD effects, and mechanisms of action of several Prussian blue nanozymes. PB analogues stand out for their intrinsic biocompatibility (Fe-based; FDA-approved for other indications), multimodal ROS scavenging, and ease of doping to introduce additional functionalities; however, potential degradation products (eg, cyanide-related species) and long-term safety in chronic IBD models require rigorous evaluation. The doping strategy (Mn, W, Se) exemplifies how hybridizing distinct metal centers can yield synergistic or multifunctional effects—a principle broadly applicable to other nanozyme classes.

Figure 6.

(a) Iron–cyanide-based nanomaterials alleviate IBD by regulating ROS and M1/M2 balance. Red upward arrow indicates increased M1 and M1/M2 ratio; red downward indicates reduced pro-inflammatory cytokines (TNF-α, iNOS, IL-1β); blue upward indicates increased M2 and anti-inflammatory cytokines (Arg-1, IL-10); blue downward indicates decreased M1/M2 ratio. Reproduced with permission from Ref.84 Copyright 2025, RSC. (b) W-PB nanoparticles alleviate colitis by inhibiting Enterobacteriaceae and modulating cGAS–STING. Two pathways are shown: red arrows (pro-inflammatory) – red upward indicates increased IFN-γ/TNF-α secretion, red downward indicates reduced Treg number/function; green arrows (anti-inflammatory) – green downward indicates reduced IFN-γ/TNF-α, green upward indicates increased Treg number/function. W-PB, tungsten-doped Prussian blue; cGAS–STING, cyclic GMP-AMP synthase–STING pathway. Reproduced with permission from Ref.85 Copyright 2025, Elsevier.

Table 3.

Comparison of Different Prussian Blue Analogue Nanozymes

Prussian Blue-Based Nanozymes	Structural/Compositional Characteristics	Main Functions	Gastrointestinal Stability/Targeting Design	Anti-IBD Effects	Ref
Zero-valent selenium-loaded Prussian blue nanozyme (Se0-PB nanozyme)	PB loaded with zero-valent selenium; with an average particle size of 62 nm	Antioxidant; anti-ferroptosis; immunomodulation	Selenium-iron layer resists gastric acid; CD44 binding prolongs retention of nanozyme	Reduced ROS, LPO and Th17 cells	[83]
Ultrasmall Prussian blue nanodots (UPB)	Average particle size 3.1 nm; with high specific surface area	ROS scavenging; macrophage polarization regulation	Not mentioned	Alleviated inflammation; exhibited catalytic activity higher than conventional PB	[84]
Tungsten-doped Prussian blue (W-PB) nanoparticles	Tungsten element doping modification	ROS scavenging; microbiota regulation	Not mentioned	Achieved long-term remission of colitis	[85]
Manganese-doped Prussian blue nanozymes (MPBZs)	Precisely controlled composition and morphology; retains PB framework structure	Cascade ROS scavenging; colloidal stability	Resists gastric fluid/digestive enzymes; enriches in inflamed region	Reduced oxidative stress without liver or kidney dysfunction	[86]
Pure-phase Prussian blue nanozyme (PB nnanozyme)	Triple enzyme-mimetic system constructed by regulating crystal growth; with an average particle size of 45 nm	ROS scavenging; bactericidal effect; barrier repair; microbiota regulation	Hydration layer resists gastric acid; electrostatic interaction prolongs retention	Reduced ROS and pro-inflammatory cytokines; increased tight junction proteins	[87]

Organic/Polymer-Based Nanozymes

Organic/polymer-based nanozymes generally exhibit better biodegradability and more versatile chemical modification sites. For example, Xu et al⁸⁶ constructed diselenide-bridged hyaluronic acid nanogels. This material uses hyaluronic acid as the backbone, crosslinked via diselenide bonds to form nanogels. Hyaluronic acid can specifically target the CD44 receptor—which is overexpressed in inflamed tissues—enabling active, targeted delivery to the inflamed colon tissue. The diselenide bonds not only confer ROS-responsive properties (they are cleaved under high-ROS conditions to enable controlled drug release) but also possess intrinsic ROS-scavenging capacity, directly eliminating hydroxyl radicals (•OH) and other ROS; this nanogel was shown to upregulate the intracellular Nrf2/HO-1 antioxidant pathway. In a mouse model of colitis, treatment with this nanogel resulted in a significant decrease in colonic ROS levels and marked improvement in inflammation scores. Zhang et al⁸⁸ fabricated a composite material by modifying cerium oxide with polydopamine. This material combines the advantages of nanozymes and organic coatings: the core cerium oxide provides superoxide dismutase– and catalase-mimicking activity, while the polydopamine shell further enhances ROS removal through its catechol structure. It also exerts direct anti-inflammatory effects by inhibiting inflammatory signaling pathways such as TLR4/NF-κB; thus, it demonstrates synergistic antioxidative and anti-inflammatory effects.

Organic-based nanozymes excel in active targeting and stimulus responsiveness, but their catalytic efficiency is generally lower than that of metal-based counterparts. They are better suited for combination therapies (eg, drug delivery coupled with ROS scavenging) rather than standalone antioxidant catalysis. Their biodegradability confers a distinct safety advantage; however, the long-term fate of degradation products (eg, selenium species) remains to be clarified. Unlike metal-based nanozymes that primarily operate through direct catalytic ROS scavenging, organic/polymer-based materials often rely on a combination of direct chemical scavenging (via functional groups such as selenides, catechols, or thiols) and activation of endogenous antioxidant pathways such as Nrf2/HO-1. Although these materials are commonly classified as “nanozymes” in the literature, their mechanism is more accurately described as that of “antioxidant nanomaterials” or “ROS-scavenging polymers,” as they do not necessarily replicate the catalytic cycle of a specific natural enzyme.

MOF-Based Nanozymes

Metal–organic framework (MOF) materials possess advantages such as high porosity, large specific surface area, and controllable structure, which enable loading of oxidative or anti-inflammatory active components and integration of multiple functions.⁸⁹ The biocompatibility and biodegradability of MOF-based nanozymes are design-dependent properties rather than inherent characteristics of the entire material class. MOFs constructed from biologically essential metal ions (eg, Fe³⁺, Mn²⁺, Zn²⁺) and biodegradable organic ligands (eg, endogenous nucleotides, amino acids, or simple organic acids) can degrade under physiological conditions into non-toxic or metabolizable byproducts, minimizing long-term toxicity concerns. Conversely, MOFs containing non-essential metals or non-biodegradable ligands may exhibit poor biocompatibility and prolonged retention. Therefore, the safety of MOF nanozymes must be evaluated on a case-by-case basis, considering the specific metal nodes, organic ligands, and their respective degradation products, rather than assumed as a class-wide property.^90,91 Zhao et al⁹² developed manganese-based metal–organic framework (Mn-MOF) microcapsules via microfluidic encapsulation technology. Using phosphoserine—a naturally occurring cell membrane component—as the organic ligand, manganese ions coordinate with phosphate groups to construct the MOF scaffold, ensuring excellent biocompatibility. The resulting Mn-MOF was then encapsulated in alginate microcapsules using microfluidic electrospray technology to form a core–shell architecture. Upon reaching the neutral to weakly alkaline environment of the intestine, the alginate shell undergoes swelling or dissolution, enabling controlled, site-specific release of the Mn-MOF at inflamed sites. The released Mn-MOF displays catalase-like activity, effectively scavenging excessive ROS and protecting intestinal epithelial cells from oxidative injury (Figure 7a).

Figure 7.

(a) Mn-MOF decomposes H₂O₂ via catalase-like activity for antioxidative therapy. Mn-MOF, manganese-based metal–organic framework; CAT, catalase. Reproduced with permission from Ref.93 2021, Elsevier Ltd. (b) MOF-818 targets the gut microbiota, scavenges O₂⁻ and H₂O₂, and repairs the intestinal barrier. In panle (b), upward and downward arrows indicate elevation and suppression, respectively, with red arrows denoting detrimental effects and green arrows denoting protective effects. Reproduced with permission from Ref.94 2025, American Chemical Society.

Hu et al⁹³ developed a MOF-818 nanozyme with dual-metal active sites and a mesoporous structure, employing copper nitrate and zirconium oxychloride as metal nodes and pyrazolecarboxylic acid as the organic ligand. Within this nanozyme, copper ions exhibit superoxide dismutase– and catalase-mimicking activities. Oral delivery of this material markedly attenuated inflammation and mitigated intestinal oxidative injury in a murine model of DSS-induced colitis (Figure 7b). MOF nanozymes offer a highly modular platform for integrating multiple catalytic functions and controlled release; however, their synthetic complexity and batch-to-batch reproducibility remain major barriers to scale-up. Moreover, the stability of MOF structures in gastrointestinal fluids—despite some protective coatings—has not been systematically benchmarked against that of inorganic or Prussian blue (PB) nanozymes.

Based on a comprehensive review of the IBD nanozyme literature published from 2019 to the present, covering all major material classes—including inorganic nanozymes (Mn₃O₄, Mo₃Se₄, RuCo, Ni₃S₄), Prussian blue and analogues, organic/polymer-based nanozymes, and MOF-based nanozymes—we found that the vast majority of reported studies (n = 34 across all classes, as summarized in Tables 2–4) rely on short-term acute colitis models (DSS or TNBS, typically 7–14 days). To our knowledge, no study has yet provided longitudinal safety data (≥3 months) or efficacy data in relapsing or chronic IBD models (Table 4). This constitutes a field-wide blind spot that has been independently noted in recent reviews on nanozyme applications in IBD. Moreover, direct head-to-head comparisons between different nanozyme classes under identical experimental conditions are completely absent, making it impossible to judge which platform truly outperforms others for specific patient subsets. In summary, nanozymes offer a powerful mechanism-driven approach to counteract oxidative stress in IBD. However, the field must move beyond the current “catalogue of novel materials” phase and embrace systematic comparison, chronic model validation, and rational hybrid design. The doping approaches seen in PB analogues (Mn, W, Se) and the coating strategy in polydopamine–ceria represent early examples of such hybridization.

Table 4.

The Advantages and Limitation of Different Nanozyme Classes

Design Principle	Inorganic (Excl. PB)	PB Analogues	Organic/Polymer	MOF
Core catalytic mechanism	Metal valence cycling (Mn, Mo, Ru, Zn)	Fe2⁺/Fe3⁺ cycling + doping (Mn, W, Se)	Diselenide, catechol, Nrf2 pathway activation	Metal nodes (Mn, Cu) + porous scaffold
Primary advantage	High catalytic efficiency, simple synthesis	Biocompatible, multimodal, clinically familiar	Biodegradable, targetable, responsive	Modular, high porosity, multi-functional
Key limitation	Metal toxicity uncertainty	Cyanide-related degradation products	Lower catalytic turnover	Synthetic complexity, stability concerns
Reported models	Acute DSS (2–14 days)	Acute DSS	Acute DSS	Acute DSS
Readiness for chronic validation	Low	Medium	Low	Very low

Probiotic Nanodelivery Systems for Regulating Gut Microbiota

The imbalance of gut microbiota homeostasis is another important feature and driving factor in the occurrence and development of IBD.⁹⁴ Patients with IBD often exhibit decreased microbiota diversity, increased abundance of pro-inflammatory bacteria (such as Enterobacteriaceae, Proteobacteria), and significantly reduced abundance of beneficial bacteria with anti-inflammatory and barrier repair functions (such as Bifidobacterium, Lactobacillus, and Faecalibacterium).^86,95 This microbiota imbalance can disrupt the intestinal epithelial barrier, activate abnormal immune responses, and form a vicious cycle with oxidative stress and immune disorders, jointly promoting the disease progression.⁹⁶

Supplementation of probiotics is a direct means to regulate the balance of the microbial community.^97,98 Oral administration of free probiotics faces severe challenges. The vast majority of probiotics are extremely sensitive to gastric acid and bile salts, and are largely inactivated before reaching the colon; even if they survive and reach the colon, their colonization ability is affected by the competition of the host’s original microbiota, the inflammatory microenvironment (high ROS, low pH), and the rejection of the mucosal layer, resulting in a low colonization rate and short residence time.⁹⁹ Nanotechnology provides a solution to this predicament.^100,101 According to the technical principles and delivery strategies, probiotic nanodelivery systems can mainly be classified into coating protection systems, composite carrier systems, and microenvironment-responsive dynamic systems.

Probiotic Delivery Systems with Protective Coatings

The coating-protected probiotic delivery system provides physical protection and microenvironment improvement by encapsulating nanomaterials on the surface of probiotics. For instance, Park et al¹⁰² constructed the polyphenol nanozyme armor system (ECA@EcN), which encapsulated *Escherichia coli* Nissle 1917 with gold nanozymes and was coated with chitosan-modified procyanidin–epicatechin. The chitosan-modified procyanidin–epicatechin coating—owing to its mucoadhesive properties—enhances the colonization ability of EcN in the colon, while the gold nanozymes create a favorable microenvironment for EcN survival and function. In a DSS-induced colitis mouse model, the ECA@EcN treatment group showed a significantly lower disease activity index and reduced colon pathological damage score. The levels of pro-inflammatory cytokines TNF-α and IL-6 in colon tissue decreased by approximately 60% and 50%, respectively, verifying the anti-inflammatory effect achieved through synergistic action of the nanomaterial functional unit and probiotics (Figure 8). In a related approach, Dou et al¹⁰³ developed a biomimetic nanoarmoring strategy by in situ mineralizing a uniform calcium carbonate (CaCO₃) nanocoating on the surface of E. coli Nissle 1917 preassembled with luteolin. This EcN-Lut/CaCO₃ system achieved a 100-fold increase in bacterial survival under simulated gastrointestinal conditions and enabled colon-specific delivery. The composite demonstrated potent ROS scavenging (~100%) and immunomodulatory capacity, downregulating TNF-α, IL-6, IL-1β, and IL-17A while upregulating IL-10. In DSS-induced colitis mice, the system restored colon length by 57.30% and reduced the disease activity index by 72.73%, with transcriptomic analysis revealing dual regulation of cAMP/cGMP-PKG metabolic cascades and IL-17/TNF inflammatory pathways. Liang et al¹⁰⁴ constructed a polydopamine–cerium oxide coating (PDA@CeO₂@B.B.) on the surface of *Bifidobacterium* (B.B). They leveraged the strong intestinal mucosal adhesion property of polydopamine (PDA) and the ROS-scavenging capability of CeO₂, providing a novel strategy for optimizing the targeting and functionality of bacterial surface modification.

Figure 8.

(a) ECA@EcN is constructed through phenolic–metal coordination-mediated interfacial and electrostatic interactions. (b) ECA@EcN restores the balance of the intestinal microbiota and inhibits inflammatory responses. Upward arrows indicate elevated microbial abundance or increased ROS levels, whereas downward arrows indicate reduced microbial abundance, decreased ROS production, and diminished inflammatory cytokine levels. (c) ECA@EcN mimics superoxide dismutase (SOD) and catalase (CAT) antioxidant enzymes and modulates the intestinal microbiota. Reproduced with permission from Ref.103 2025, Wiley.

Researchers have also loaded probiotics onto larger nano- or microscale carriers—either within or on their surfaces—to form composite carrier systems featuring multiple functional modules, including integrated protection, targeted delivery, and synergistic therapy. For example, Zhou et al¹⁰⁵ constructed the MnCe@LR/AMs system. This system coated a layer of manganese-doped cerium oxide nanozymes onto the surface of *Lactobacillus reuteri* then encapsulated the coated bacteria in pH-sensitive hydrogel microspheres formed from sodium alginate and methylcellulose. This design established a precise “nanozyme–probiotic–hydrogel” tripartite synergistic system: the hydrogel microspheres maintained structural integrity in the acidic gastric environment, protecting the encapsulated bacteria and nanozymes from gastric acid and digestive enzymes; upon reaching the neutral pH of the colon, the microspheres swelled and degraded, enabling colon-specific release. The nanozyme coating was continuously released to scavenge local ROS, reducing ROS levels in inflamed tissue by approximately 70% and thereby markedly improving the probiotic colonization microenvironment; concurrently, the probiotics exerted microbiota modulation and immune-regulatory functions. The survival rate of probiotics in simulated gastrointestinal fluid was approximately 15-fold higher than that of free probiotics; moreover, the retention time of the microspheres in the colons of colitis mice extended from less than 6 hours (for free bacteria) to over 48 hours. It is important to note that this extended residence time represents improved mucosal retention or delayed intestinal transit, not true colonization. Stable colonization requires long-term persistence of the probiotic strain in the gut lumen or mucosal surface without continuous administration, typically demonstrated through strain-specific tracking (eg, via genetic markers or antibiotic resistance profiling) over weeks to months. While 48-hour retention is a meaningful improvement for local drug delivery and transient therapeutic effects, it should not be conflated with colonization, which requires evidence of sustained replication and engraftment within the host microbiota ecosystem, and the inflammation score in the treatment group was approximately 40% lower than that of the free-probiotic control group. Hu et al¹⁰⁶ formed the pBDT–TA polyphenol nanocarrier via self-assembly of tannic acid (TA) and self-polymerized aromatic disulfide (BDT), then modified the EcN surface using layer-by-layer coating with sodium alginate (SA) to construct the EcN@SA–pBDT–TA system. In this system, pBDT–TA scavenged ROS via phenolic hydroxyl and thiol groups, and also downregulated pro-inflammatory cytokines (TNF-α and IL-1β decreased by approximately 55% and 50%, respectively) and inhibited the NF-κB pathway. Compared with the MnCe@LR/AMs system, this system demonstrated a unique advantage: “multitarget anti-inflammatory properties conferred by polyphenolic materials”; additionally, the alginate shell enhanced probiotic survival.

Microenvironment-Responsive Probiotic Delivery Systems

Microenvironment-responsive dynamic systems aim to dynamically regulate the probiotic delivery process according to the intestinal microenvironment, enabling release at “the right time and the right place.” For example, the “Probiotic Backpack” system (HPN-NE-EcN) developed by Liu et al¹⁰⁷ uses engineered *Escherichia coli* Nissle 1917 as the “chassis”, which is “backpacked” with curcumin-loaded mesoporous silica nanoparticles via ROS-responsive thioketal linkers on the bacterial surface. Upon arrival at the inflamed colon—a high-ROS environment—the thioketal linkers are cleaved, leading to detachment of the nanoparticle “backpack” and release of curcumin, thereby reducing local oxidative stress levels by approximately 65% within 4 hours. Meanwhile, the “backpack”-removed EcN surface becomes coated with polynorepinephrine, which exhibits strong mucoadhesive properties and promotes preferential colonization of EcN at the site of inflammation, achieving an approximately three-fold increase in colonization compared to non-responsive systems. This sequential strategy— “first antioxidant clearance, then probiotic colonization” —significantly enhances the precision and efficiency of intervention. In addition to delivering a single strain, researchers have also attempted simultaneous delivery of multiple strains (Figure 9). For instance, Shen et al¹⁰⁸ constructed a glutathione-enriched probiotic–nanoparticle composite (BANPs) system. The introduction of glutathione enhanced the system’s ROS-scavenging capacity and provided favorable conditions for probiotic survival in the inflammatory microenvironment. By combining antioxidant supplementation with probiotic colonization, this system offers a new paradigm for upgrading probiotic nanodelivery systems—from simple live-bacterial supplementation to “metabolic microenvironment remodeling coupled with live-bacterial intervention.”

Figure 9.

(a) Preparation of HPN via self-assembly of HA–PPS molecules, encapsulation of Escherichia coli Nissle 1917 (EcN) with a norepinephrine (NE) layer, and conjugation of the resulting HPN to the EcN surface. (b) Comparison of the IBD state (left) and the therapeutic state (right) in the intestinal microenvironment. In the IBD state, the intestinal wall is damaged, reactive oxygen species (ROS) are released, pathogenic bacteria proliferate, and an inflammatory response occurs. In the therapeutic state, HPN-NE-EcN exerts its effects through three sequential steps: (i) ROS scavenging, (ii) adhesion to the damaged intestinal wall, and (iii) bacteriotherapy to eliminate pathogenic bacteria. (c) Detailed microscopic mechanisms of the three steps. (i) ROS scavenging: the sulfur bonds in PPS are oxidized, thereby consuming and neutralizing harmful ROS. (ii) Adhesion: phenolic hydroxyl groups interact with the intestinal cell surface, enabling effective retention and targeted colonization of the composite material in the gut. (iii) Bacteriotherapy: EcN eliminates pathogenic bacteria (marked with red circles), thereby modulating the gut microecology and restoring microbial balance. Reproduced with permission from Ref.107 2022, American Association for the Advancement of Science.

Despite these promising preclinical advances, it is important to contextualize the current translational status of nanomedicine probiotic formulations. Conventional oral probiotics face three major limitations in IBD: massive loss of viable bacteria during GI transit, poor colonization due to competition from native microbiota and the mucosal barrier, and inconsistent therapeutic responses due to strain-sensitivity variability. Nanomedicine formulations are designed to address these issues through protective encapsulation, targeted delivery to inflamed sites, and integration of multiple functional modules—including ROS-scavenging nanozymes to create a favorable microenvironment, surface ligands for active targeting, and temporally programmed release. However, we must acknowledge that no nanomedicine probiotic formulation has yet received clinical approval. The vast majority of studies remain preclinical; no head-to-head randomized controlled trials have demonstrated clinical superiority over traditional probiotics; and manufacturing costs and regulatory classification—whether as dietary supplements, biologics, or novel therapeutics—remain substantial barriers. From a scientific and mechanistic perspective, nanomedicine formulations represent a fundamental upgrade over the “bulk supplementation” approach of traditional probiotics, offering precision delivery, environmental responsiveness, and functional integration. But from the perspective of existing clinical evidence and practical application, this potential has not yet been realized. Without head-to-head trials, we cannot claim superiority over market-tested, safe, and cost-competitive commercial products. Thus, the designs discussed in this section should be viewed as emerging strategies for next-generation probiotic delivery rather than validated clinical alternatives to current commercial products, and advancing clinical translation remains the primary priority.

Combination Therapy Strategies

The pathogenesis of IBD involves multiple interrelated pathological processes, including oxidative stress, immune dysregulation, gut microbiota imbalance, and epithelial barrier dysfunction. Single-mechanism therapeutic strategies (eg, ROS scavenging alone or single anti-inflammatory drug delivery) are often insufficient to achieve durable clinical remission. In recent years, combination therapy strategies have emerged as one of the most active research directions in IBD nanotherapy.

Multi-Drug Co-Delivery Nano-Platforms

Co-loading two or more drugs with complementary mechanisms of action or distinct physicochemical properties into a single nanocarrier enables mechanistic synergy (eg, anti-inflammatory plus antioxidant), dose reduction (synergistic effects lower the effective dose of each individual drug, minimizing systemic side effects), and optimized pharmacokinetic matching.

To achieve such synergy, one strategy involves the co-delivery of a conventional drug and a phytochemical. In this context, Duan et al¹⁰⁹ prepared thiolated chitosan/alginate composite microparticles co-loaded with 5-ASA and curcumin, with an outer coating of the pH-sensitive polymer Methacrylic Acid Copolymer, Type B. This coating remains intact at pH < 7 and dissolves upon reaching the colon (pH ≥ 7), triggering the release of both therapeutics. The mucoadhesive properties of the system arise from disulfide bond formation between thiol groups and mucus glycoproteins. The pH-sensitive coating ensures colon-specific release, while 5-ASA (a conventional anti-inflammatory aminosalicylate) and curcumin (a natural hydrophobic polyphenol with antioxidant and anti-inflammatory activities) produce synergistic effects through complementary inhibition of the NF-κB pathway at both upstream and downstream nodes.

A distinct colon-targeted system was developed by encapsulating Cu–Mn₃O₄ nanozymes in calcium alginate hydrogel microspheres (termed HMCM).¹¹⁰ The calcium alginate hydrogel microspheres resist gastric fluid degradation and specifically dissolve in the colonic microenvironment for precise release. The mixed valence states of Mn²⁺/Mn³⁺ and Cu⁺/Cu²⁺ confer triple enzyme-mimetic activities (SOD, CAT, and GPx), enabling efficient and broad-spectrum ROS scavenging. Simultaneously, the system promotes macrophage M1→M2 polarization, modulates pro-inflammatory (TNF-α, IL-1β, IL-6) and anti-inflammatory (IL-10) cytokine levels, remodels gut microbiota homeostasis, upregulates tight junction proteins (claudin, ZO-1, occludin), and inhibits colonic epithelial cell ferroptosis. Notably, biodistribution studies confirmed no accumulation in other organs and no detectable toxicity.

While multi-nanozyme systems rely on inorganic catalytic activities, an alternative strategy employs metal–natural product coordination to achieve synergistic therapeutic effects. Fu et al¹¹¹ designed copper ion–luteolin nanocomplexes (CuL NCs) via a metal–polyphenol coordination strategy. This natural product–based nanoplatform exhibits multiple therapeutic functions: efficient ROS scavenging through activation of the Nrf2/HO-1 oxidative stress pathway; NF-κB pathway modulation to reduce pro-inflammatory cytokine levels; protection of intestinal epithelial cells and promotion of mucosal barrier repair; and regulation of gut microbiota balance. In both UC and CD mouse models, CuL NCs demonstrated significant preventive and therapeutic effects, highlighting the potential of metal–natural product coordination chemistry for multi-pathology intervention in IBD.

Nanozyme + Probiotic Combination Therapy

In the context of nanotherapeutic strategies for IBD, nanozyme–probiotic combination therapy has emerged as a novel and promising research direction. In this sequential mode of action, nanozymes first act to clear excessive ROS at the inflammatory site, reducing local oxidative stress and creating a favorable microenvironment for subsequent probiotic colonization. Once established, the colonized probiotics then provide sustained therapeutic benefits by secreting short-chain fatty acids (SCFAs), regulating immune cell polarization, and restoring microbial diversity, thereby repairing the intestinal barrier and reestablishing immune homeostasis. A representative example is the MnCe@LR/AMs system,¹⁰⁴ in which manganese-doped cerium oxide nanozymes (Mn@CeO₂) were conjugated to the surface of *Lactobacillus reuteri* and further encapsulated in alginate microspheres, achieving integrated triple functionality—protection, targeting, and antioxidant activity. The system has a three-layer design: the outer alginate microspheres protect against gastric acid and target inflamed areas via negative charge and mannose receptors; the middle Mn@CeO₂ nanozyme layer scavenges ROS through manganese redox cycling; and the core *L. reuteri* produces SCFAs that promote regulatory T cells and repair the gut barrier. In vivo, the system lowered disease activity, increased tight junction proteins, and restored goblet cells to near-normal levels. Metabolomics showed higher tryptophan metabolites and lower oxidized glutathione, while transcriptomics revealed activation of amino acid metabolism pathways.

In a related approach, direct ROS scavenging is combined with pH-responsive targeting. In one such design, CeO₂ nanozymes are covalently conjugated to the surface of *Escherichia coli* Nissle 1917 (EcN) via a bioorthogonal SPAAC reaction, with an outer coating of the pH-responsive anionic copolymer Eudragit L100-55 (the CeO₂@EcN/L system).¹¹² In this system, CeO₂ nanozymes possess both SOD and CAT mimetic activities; the Eudragit coating confers pH-responsive adhesive capacity—its negatively charged surface selectively binds to positively charged inflamed colonic tissue via electrostatic interactions. In a DSS-induced IBD mouse model, this system effectively cleared ROS and restored gut microbiota homeostasis. More distinctively, beyond direct ROS scavenging, a metabolically coupled system has been developed.

A bioactive composite system (FePL) has been constructed by combining FeNGR nanozymes with *Lactococcus lactis*.¹¹³ In this system, Fe–N-doped graphene (FeNGR) nanozyme exhibits NADH oxidase–mimetic activity, catalyzing the conversion of NADH to NAD⁺. The key feature is the metabolic coupling between the probiotic and the nanozyme: *L. lactis* colonizes the intestine and continuously secretes NADH (an ideal long-term supplier), while FeNGR efficiently converts it to NAD⁺. The elevated NAD⁺ then induces apoptosis of tissue-resident memory T cells via the ART2–P2X7 axis, thereby eliminating a major source of persistent inflammation in IBD.

Collectively, these examples illustrate that the nanozyme–probiotic combination strategy operates through a temporally programmed “clearance then colonization” mechanism. Nanozymes transiently modulate the inflammatory microenvironment to permit probiotic engraftment; after which, the probiotics provide sustained therapeutic benefits that extend beyond the short half-life of the nanozyme components. This hierarchical design represents a promising paradigm for achieving both rapid ROS scavenging and long-term mucosal healing in IBD.

Candidate Nanomaterials

The selection of appropriate materials is a critical determinant in the construction of nanoscale targeted therapeutic systems for IBD. Synthetic nanomaterials and natural product-based nanomaterials differ in their physicochemical properties and biocompatibility, which in turn dictate their distinct mechanisms of action and safety profiles.

Synthetic Nanomaterials

Due to their superior targeted delivery capabilities and redox catalytic activities, synthetic nanomaterials—such as Mn₃O₄, Prussian blue, and PLGA nanoparticles—are widely employed in IBD nanotherapy. Metal-based nanozymes constructed from Mn₃O₄ scavenge ROS through valence-state cycling, offering advantages including high catalytic efficiency and relatively well-established preparation processes. Nevertheless, the long-term accumulation toxicity of Mn₃O₄ requires careful consideration. Manganese-based nanomaterials require careful dose optimization to balance therapeutic efficacy against potential toxicity. In mice, Mn₃O₄ nanoparticles at ~125 mg/kg enhanced colonic antioxidant capacity without adverse effects over 20 days, whereas 250 mg/kg caused oxidative damage. For human context, the NIH has set a tolerable upper intake level of 11 mg/day for dietary manganese, with whole-blood concentrations >15 μg/L associated with neurotoxicity risk. However, no direct comparison can be made between dietary intake limits and acute therapeutic doses, as these represent fundamentally different exposure scenarios—chronic dietary intake versus short-term pharmacological administration. The long-term safety of chronic manganese-based nanozyme administration, particularly in patients with impaired biliary excretion, remains uncharacterized, and interspecies differences in metabolism and neurotoxicity susceptibility limit direct translation of murine data to humans. Systematic evaluation of cumulative dose effects and chronic exposure outcomes is urgently needed.

Prussian blue (PB) possesses well-documented human safety data and a clearly defined pharmacokinetic profile, and has received approval from the US Food and Drug Administration (FDA) for the treatment of thallium or radioactive cesium poisoning.¹¹⁴ The core metal of PB nanoparticles is iron, an essential trace element for the human body, whose intracellular levels are tightly regulated via the hepcidin–ferroportin pathway.¹¹⁵ The open metal–organic framework (MOF) architecture of Prussian blue analogs (PBAs) enables gradual dissociation under physiological conditions, thereby conferring a low risk of long-term retention. Doping with functional elements such as manganese (Mn–PB), selenium (Se⁰–PB), or tungsten (W–PB) markedly enhances the ROS-scavenging activity of PBAs and imparts the capacity to inhibit ferroptosis. Nevertheless, the safety profile of these doped elements requires careful consideration. Although some researchers propose that an optimal balance between therapeutic efficacy and safety can be achieved through rational design—including controlled doping ratios, optimized crystal dimensions, and sustained release strategies—this remains a critical concern that merits further investigation.¹¹⁶

PLGA (poly(lactic-co-glycolic acid)) is an FDA-approved, biodegradable synthetic polymer. In contrast to the two aforementioned classes of nanozymes, PLGA itself lacks intrinsic enzyme-mimetic catalytic activity. Nevertheless, it functions as a delivery vehicle for nanozymes and is frequently employed to encapsulate nanozymes exhibiting SOD/CAT-mimetic activities—such as EUK-134 and platinum-doped carbon nanodots (PtCDs)—thereby enabling the construction of composite platforms that synergistically combine targeted delivery with cascade catalytic functions. PLGA is inherently biodegradable, and its degradation products (lactic acid and glycolic acid) can enter the tricarboxylic acid (TCA) cycle, ultimately being converted into CO₂ and H₂O.¹¹⁷

Natural Product-Based Nanomaterials

Natural product–based nanomaterials have attracted widespread interest owing to their favorable biocompatibility and low toxicity. Certain plants spontaneously produce nanostructured vesicles or vesicle-like analogs that exhibit the dual attributes of “inherent targeting capability” and “low immunogenicity.” *Coptis chinensis*–derived extracellular vesicle–like nanoparticles (Cc–ELNs) exemplify these features. Xu et al¹¹⁸ utilized Cc–ELNs as delivery vehicles for microRNA-5106 (miR-5106) to target neutrophils at sites of inflammation. By restoring intracellular zinc ion homeostasis, these nanoparticles specifically suppress the aberrant formation of neutrophil extracellular traps (NETs), thereby mitigating NETs–mediated intestinal epithelial damage and inflammatory cascade reactions. Safety evaluation demonstrated that seven consecutive days of administration (100 mg/kg/day) caused no organ toxicity or hematological abnormalities. Cao et al¹¹⁹ developed ginseng–derived nanoparticles (GDNPs)—natural nanovesicles directly isolated and purified from ginseng roots, stems, and leaves. Oral administration of GDNPs (200 mg/kg/day) to DSS–induced colitis mice for 14 consecutive days resulted in serum ALT and AST levels comparable to those of healthy controls, with no notable histopathological alterations in the liver or kidney tissues. Plant-derived extracellular vesicles possess inherent intestinal targeting properties and generally exhibit low immunogenicity under controlled conditions, but their safety profile is not assured by natural origin alone. Several challenges complicate their clinical translation. Plant-derived vesicles are particularly challenging to produce at scale: yields are typically low, purification protocols require multiple ultracentrifugation or chromatography steps to achieve acceptable purity, and residual solvents or processing agents from isolation may introduce additional toxicity risks. Moreover, these vesicles naturally carry exogenous nucleic acids (including RNA species) and proteins that may trigger immune responses, especially in IBD patients with a hyperactive mucosal immune system. Batch-to-batch variability arises from differences in cultivation conditions, harvest seasons, and extraction methods, which affect vesicle composition and biological activity. Currently, these materials remain in the stage of basic research, and rigorous safety evaluation—including immunogenicity testing, nucleic acid profiling, endotoxin assessment, and characterization of batch consistency—is essential before clinical translation can be considered.¹²⁰

Polyphenolic compounds are characterized by abundant phenolic hydroxyl groups, which readily coordinate with metal ions or participate in intermolecular interactions to form stable nanostructures.^74,121 In addition to their structural versatility, polyphenols possess multifaceted biological activities—including antioxidant, anti-inflammatory, and antibacterial properties—making them an ideal candidate reservoir for IBD therapy.^122,123 Jin et al¹²⁴ exploited the coordination between polyphenols (eg, tannic acid) and metal ions (eg, Fe³⁺) to construct stable nanoparticles capable of encapsulating hydrophobic bioactive molecules such as curcumin (Figure 10). The polyphenol–metal coordination architecture gradually dissociates in the weakly alkaline environment of the intestine, facilitating the sustained release of curcumin and Fe³⁺ and thereby overcoming the long–standing delivery obstacles associated with curcumin. In this system, tannic acid and curcumin synergistically inhibit the NF-κB signaling pathway, while Fe³⁺ mimics CAT-like activity to catalyze the degradation of H₂O₂. From a safety perspective, 14 days of treatment with this system resulted in no detectable serum iron accumulation or hepatic iron overload.

Figure 10.

(a) Chemical structures of representative polyphenols—EGCG (epigallocatechin gallate), TA (tannic acid), and GA (gallic acid)—highlighting their multiple hydroxyl groups. (b) Schematic illustration of the interfacial interaction mechanisms between polyphenols (black clusters) and iron ions (Fe³⁺, red spheres) at a microbial surface under alkaline conditions (pH > 7). Two distinct interaction modes are shown: (i) polyphenol–microbe interactions, where non-covalent forces—including hydrogen bonding, π–π stacking, and hydrophobic interactions—drive the association between polyphenols and the microbial surface (represented by the polymer chain); and (ii) polyphenol–Fe(III) interactions, where metal–phenolic coordination (chelation) bonds form between the hydroxyl groups of polyphenols and Fe³⁺ ions, yielding a stable complex. Reproduced with permission from Ref.124 2025, Elsevier Ltd.

Inulin, sodium alginate, chitosan, gelatin, and rhein—representative natural or naturally derived materials—are widely employed in the fabrication of hydrogels featuring three–dimensional hydrophilic network structures.¹²⁵ These hydrogels can encapsulate therapeutic agents or nanoparticles, shielding them from degradation by gastric acid and digestive enzymes.¹²⁶ By leveraging a “nanoparticle–in–hydrogel” composite delivery system, controlled drug release within the colon can be reliably achieved.^127,128 Among these materials, inulin, sodium alginate, and chitosan have emerged as the three most extensively investigated natural hydrogel matrices for IBD–targeted therapy, attributable to their distinctive properties: inulin is specifically degraded by colonic microbial enzymes, sodium alginate exhibits pH–responsive gelation behavior, and chitosan provides mucoadhesive properties and a positive surface charge. As a representative example, Fan et al¹²⁹ developed an oral nanocomposite hydrogel delivery system by embedding curcumin–loaded, chitosan–coated PLGA nanoparticles into an inulin hydrogel matrix. In this system, the inulin hydrogel serves a dual role: it protects the nanoparticles from gastric degradation, significantly extending the colonic retention time of curcumin, while concurrently contributing to the modulation of gut microbiota homeostasis in DSS–induced colitis mice.

Beyond pH–responsive systems, ROS–responsive hydrogels have also been designed to achieve more precise on–demand drug release at the inflamed site. For example, Xiong et al¹³⁰ developed a diselenide–bridged arctigenin–chitosan hydrogel (ATG–CS–Gel). This hydrogel leverages the mucoadhesive properties of chitosan to enable colonic retention of arctigenin for up to 24 hours. The diselenide bonds are cleaved under conditions of high ROS levels, thereby achieving “on–demand” drug release. In vivo experiments demonstrated therapeutic efficacy superior to that of 5–aminosalicylic acid (5–ASA). The underlying mechanism involves the blockade of MLCK activation and the upregulation of tight junction protein expression, leading to the repair of the intestinal mucosal barrier.

These findings underscore the favorable safety profile and therapeutic potential of natural product–based nanomaterials as standalone therapeutic agents. Their intrinsic catalytic activity is often limited compared to synthetic counterparts, prompting the development of hybrid strategies that combine the strengths of both material classes.

Combined Application of Natural Product-Based Nanomaterials and Synthetic Nanomaterials

As an important strategy to circumvent the respective drawbacks of natural product–based nanomaterials and synthetic nanomaterials, the integration of these two material types has been widely explored for colon–targeted drug delivery. A commonly adopted approach involves using natural–derived polysaccharides (eg, chitosan, sodium alginate) or polyphenols as surface coatings, with synthetic nanomaterials (eg, Prussian blue, metal–organic frameworks) as the inner core. This design preserves the high catalytic activity of the synthetic core while leveraging the biocompatibility and targeting capability of the natural coating to reduce toxicity and prolong circulation time.

The integration of natural and synthetic nanomaterials follows two complementary design paradigms at different length scales: nanoscale core–shell coating and macroscale hydrogel encapsulation. In the former paradigm, natural materials (chitosan, alginate, polyphenols) are coated onto individual synthetic nanoparticles (Prussian blue, MOFs, PLGA nanoparticles) to confer mucoadhesion, biocompatibility, and active targeting. In the latter paradigm, nanoparticles or engineered probiotics are embedded within natural hydrogel matrices (alginate, inulin, chitosan). The hydrogel serves as a protective depot: it shields cargo from gastric acid and enzymes, enables sustained colonic retention (>48 hours), and certain hydrogels (eg, inulin) provide prebiotic activity. These two paradigms are often combined, as nanoscale coating enhances nanoparticle functionality while macroscale encapsulation ensures safe oral delivery and prolonged colonic residence.

Several studies have demonstrated the utility of the core–shell coating paradigm. For instance, a composite system was constructed by coating metal nanozymes with polyphenols, achieving synergistic therapeutic effects encompassing ROS scavenging and gut microbiota regulation.¹³¹ In another study, chitosan–PLGA nanoparticles encapsulating curcumin were developed, where the chitosan shell confers mucoadhesive properties and biocompatibility.

The hydrogel encapsulation paradigm has also been validated in various systems. Leveraging the ability of rhein—a natural anti–inflammatory component—to directly self–assemble into a pH–responsive hydrogel under weakly alkaline conditions, researchers have constructed a rhein–CeO₂ composite hydrogel incorporating CeO₂ nanozymes. In this system, rhein serves dual roles as both an anti–inflammatory therapeutic agent and a delivery vehicle for the nanozyme, enabling efficient clearance of ROS in the inflamed colon.¹³²

Notably, these two paradigms are not mutually exclusive; rather, they can be integrated to achieve synergistic effects. The aforementioned chitosan–PLGA nanoparticles encapsulating curcumin were further embedded into an inulin hydrogel, achieving triple synergistic effects: colon–targeted delivery, anti–inflammatory activity, and modulation of the gut microbiota. Similarly, polyphenol–coated metal nanozymes have been incorporated into inulin hydrogels to combine core–shell protection with macroscale encapsulation.

Beyond these two design paradigms, additional modification strategies have been employed to further enhance the performance of integrated nanosystems. For example, researchers have utilized natural nanovesicles or plant–derived nanoparticles as scaffolds, modifying them with PEGylation to prolong systemic circulation time or introducing fluorescent labels (eg, near–infrared fluorescent dyes such as Cy5 and FITC) to enable real–time tracking and imaging monitoring of nanoparticle biodistribution, targeted accumulation at inflammatory sites, and cellular uptake behavior.¹³³

Collectively, these strategies provide feasible engineering pathways to simultaneously enhance biocompatibility and therapeutic efficacy, representing a pivotal direction for advancing the development of nanomedicine–based IBD therapy.

Building on the material-by-material analysis above, a comparative assessment of translational readiness across the three major material classes reveals a clear hierarchy. We rank Prussian blue (PB) analogues as the front-runner, given their established FDA approval, WHO Essential Medicines List listing, well-defined human safety profile, and straightforward synthesis—with the caveat that doped variants require independent toxicological evaluation. Combination systems (eg, nanozyme–probiotic co-administration) rank second, offering synergistic benefits that address multiple IBD pathologies simultaneously, but lacking long-term safety data and facing manufacturing complexity. Natural product-based platforms, while promising long-term due to their inherent biodegradability and intestinal targeting properties, face batch variability and purification challenges that limit near-term translation. For each platform, we have outlined specific steps required to advance clinical translation throughout the preceding sections: PB analogues require chronic model validation and doping element safety assessment; combination systems need long-term biosafety data and optimized dosing protocols; and natural products demand standardized extraction and purification protocols alongside rigorous immunogenicity evaluation. This comparative framework informs the safety considerations discussed in the following section and the translational priorities articulated in the Conclusion.

Systematic Evaluation of Material Safety

The safety profile of nanomaterials is the cornerstone of their clinical translation. Different material classes exhibit distinct in vivo fates and toxicological characteristics. Based on a comprehensive analysis of current evidence, the following comparative assessment is provided.

Prussian blue (PB) is one of the few nanomaterials already approved by the US FDA for clinical use, specifically for the treatment of thallium or radioactive cesium poisoning. Its safety profile is characterized by predominant biliary excretion, a half-life of approximately 2–3 weeks, and minimal systemic absorption following oral administration. Toxicological studies conducted in accordance with OECD guidelines have demonstrated no significant mortality, organ toxicity, or histopathological abnormalities even at high doses (2000 mg/kg).¹³⁴ The open framework structure allows gradual degradation under physiological conditions into iron ions and cyanide complexes; the latter are converted to non-toxic cyanmethemoglobin and excreted renally. Long-term toxicity studies confirm the absence of significant hepatorenal toxicity or neurobehavioral anomalies at therapeutic doses. However, the safety of doping elements (eg, Mn, W, Se) requires independent evaluation.

In contrast to Prussian blue, manganese-based nanomaterials present a distinct safety landscape. Manganese is an essential trace element that participates in the catalytic core of superoxide dismutase (Mn–SOD). However, excessive manganese exposure carries well-defined neurotoxicity risks.¹³⁵ Mechanistic studies have revealed that manganese nanoparticles can induce blood–brain barrier disruption, cerebral blood flow reduction, brain edema formation, and subsequent cognitive and motor dysfunctions in a dose-dependent manner.¹³⁶ Long-term exposure leads to lipid peroxidation activation, reduced antioxidant system activity, and morphofunctional disorders in the brain, including nerve fiber demyelination and endothelial dystrophic changes.¹³⁷ The neurotoxicity risk is directly correlated with cumulative exposure, necessitating rigorous dose control and chronic safety evaluation.

Natural product-based materials, including polysaccharides (chitosan, alginate, inulin), polyphenols (tannic acid, epicatechin), and plant-derived vesicles, offer advantages in biodegradability, as they are gradually decomposed by gut microbial enzymes into monosaccharides or small phenolic acids for subsequent metabolism or absorption.^138,139 However, natural origin does not guarantee safety. These materials share common risk categories: source-dependent variation (different geographical origins or cultivation conditions yield distinct properties and toxicity profiles); batch-to-batch variability (harvest seasons, extraction methods, and purification processes affect chemical composition and biological activity); contamination risks (endotoxins, allergens, residual pesticides, or heavy metals co-extracted during processing); and immunogenicity (polysaccharides or vesicle components may carry immunostimulatory moieties that trigger immune responses, particularly relevant in the IBD setting where the mucosa is already dysregulated).

Compared with synthetic nanomaterials such as Prussian blue and manganese-based nanoparticles, natural materials generally present lower risk of long-term metal accumulation and offer more favorable biodegradation profiles. However, this does not make them inherently safer—they present different categories of risk that require different mitigation strategies. Synthetic materials offer controlled composition and batch consistency but carry risks of metal toxicity and non-biodegradable accumulation. Natural materials offer biodegradability but require rigorous quality control to manage variability, contamination, and immunogenicity. Systematic safety evaluation—including comprehensive characterization of composition, purity, batch consistency, and immunogenicity— remains essential for both classes and cannot be assumed based on origin alone.

Therefore, quality control should include allergen testing (eg, residual protein content and endotoxin levels) and the establishment of chemical fingerprints.

Based on the evidence reviewed above, a comparative safety profile emerges across the three material classes. Natural materials and Prussian blue exhibit favorable safety characteristics, albeit with distinct considerations: natural materials offer excellent biodegradability but require attention to allergen risks and batch–to–batch variability, whereas Prussian blue benefits from FDA approval and well–documented safety evidence, though the safety of doping elements warrants independent evaluation. Manganese–based nanomaterials, despite their therapeutic efficacy, present well–defined neurotoxicity risks that necessitate rigorous dose control and chronic safety assessment. Regardless of material class, any nanomaterial intended for IBD therapy requires systematic pharmacokinetic and toxicological evaluation in chronic IBD animal models (≥3 months) prior to clinical translation.

Beyond material-specific safety profiles, three additional safety considerations warrant attention for nanomaterial applications in IBD, where the mucosa is already inflamed and the immune system is hyperactive. First, immunogenicity depends on size, surface charge, composition, and protein corona; polymeric nanoparticles can activate complement and elicit anti-PEG antibodies upon repeated dosing, while inorganic nanoparticles may induce pro-inflammatory cytokines and activate the NLRP3 inflammasome—risks that may be amplified in IBD due to the primed mucosal immune system and leaky epithelium. Second, nanomaterials can disrupt the gut microbiome, already dysregulated in IBD, by reducing beneficial commensals while promoting pro-inflammatory Enterobacteriaceae overgrowth, and may influence horizontal gene transfer, potentially accelerating antibiotic resistance spread; conversely, commensal bacteria can participate in nanoparticle biotransformation, creating bidirectional interactions that remain poorly characterized. Third, some nanomaterials have demonstrated genotoxic potential through direct DNA damage or ROS generation, with mesoporous silica and graphene oxide inducing mutation signatures suggestive of oxidative DNA damage in vitro; in IBD, where chronic inflammation already promotes oxidative stress and patients face elevated colorectal cancer risk, additional genotoxic effects are of particular concern. No published studies have systematically evaluated the immunogenicity, microbiota disruption, or mutagenicity of IBD-targeted nanotherapies in chronic models, representing a significant knowledge gap.

Conclusion and Perspectives

Approximately 5 million people worldwide live with IBD; current advanced therapies achieve remission in only 30–50% of patients at one year, with relapse rates exceeding 50% within 12 months. The annual economic burden exceeds $6 billion in the United States alone. Even modest improvements—a 10% increase in remission rates—could benefit hundreds of thousands of patients and save billions in healthcare costs. Nanomedicine offers a pathway to such improvements; this review set out to provide a three-dimensional integrated framework—spanning how to deliver (targeting mechanisms), what to deliver (pathology-based therapeutic payloads), and what to use for delivery (smart material design)—for the rational design of nanotherapies in IBD. Throughout the preceding sections, we have examined each dimension: the evolution from passive pH-responsive systems to active targeting and multi-responsive platforms; the emergence of nanozymes, probiotic delivery systems, and combination strategies; and the comparative analysis of synthetic and natural materials. Our review confirms that progress in each dimension is necessary but none is sufficient alone to bridge the clinical translation gap.

It should be mentioned there are three critical barriers currently blocking clinical translation. First, pathophysiological features of active IBD—severe diarrhea, shortened colonic transit time, and colonic pH dropping to 2.3–5.5—are routinely overlooked in delivery system design. pH-responsive strategies risk complete failure unless calibrated against these real-world parameters.¹⁴⁰ Second, receptor-mediated targeting carries hidden liabilities; mannose receptors are highly expressed in the liver, rendering mannosylated nanoparticles potentially hepatotoxic. Third, safety assessments— especially for metal-based nanomaterials—are grossly inadequate, with most studies reporting only 2–14 days of observations and no systematic longitudinal data on biodistribution, metabolism, or chronic toxicity.

Given the limitations of single-mechanism systems, multi-responsive, hierarchically programmed nanoplatforms offer a compelling direction. A temporally programmed system can be designed with distinct functional layers: a pH-responsive enteric coating for gastric protection; an enzyme- responsive or charge-switchable intermediate layer for mucus penetration; and a ROS/GSH- responsive core for payload release. Critically, the pH-responsive layer serves a protective role—it prevents gastric degradation and is not the primary drug release mechanism. The actual payload release is governed by ROS, enzyme, or GSH triggers that remain active even in the acidic colonic microenvironment of active IBD. This distinction resolves the apparent contradiction between criticizing pH-responsive release systems while proposing pH-responsive protective coatings: the former rely on a narrow pH threshold for drug release that may be absent in active IBD; the latter provide gastric protection without depending on a specific colonic pH value for drug release. However, such sophistication introduces substantial translational challenges—increased manufacturing complexity, quality control demands, batch-to-batch reproducibility issues, and extensive regulatory characterization. Multi-responsive platforms are most justified when single-mechanism systems demonstrably fail, such as when pH-responsive systems alone are unreliable in the acidic colonic microenvironment of active IBD, when enzymatic activity varies across patients, or when a single trigger cannot achieve both tissue targeting and intracellular release. Conversely, for applications where a simpler formulation already achieves adequate therapeutic efficacy, the additional complexity may be unnecessary and counterproductive. The field should therefore adopt a problem-driven approach, selecting the minimum complexity required to address specific clinical needs.

To date, the field has developed a rich array of sophisticated nanoplatforms, yet the vast majority remain confined to proof-of-concept stages, having been validated exclusively in acute, chemically induced colitis models (7–14 days) that do not adequately recapitulate the chronic, relapsing course of human IBD. Beyond this temporal limitation, a second caveat must be acknowledged: the vast majority of preclinical studies reviewed here model the colonic mucosal inflammation characteristic of UC, not the transmural, patchy, or ileal features of CD. The extrapolation of findings to CD patients requires caution, and the development of more representative CD models is urgently needed.

Overall, we propose three priority actions to accelerate clinical translation: mandatory implementation of long-term efficacy and safety studies in chronic and relapsing IBD models (≥3 months) as a prerequisite for clinical evaluation; systematic investigation of nanomaterial biodistribution, metabolic clearance, and chronic toxicity using standardized protocols; and establishment of reporting guidelines mandating clear distinction between acute and chronic model data, explicit disclosure of batch-to-batch variability, and comprehensive physicochemical characterization. These actions are essential prerequisites for realizing nanomedicine’s potential to transform IBD care.

In conclusion, IBD nanotherapy remains in its early stages, and the gap between bench innovation and bedside application is wide. The next breakthrough will not come from incremental improvements in targeting efficiency alone, but from a fundamental rethinking of how nanotherapeutics interface with the dynamic, heterogeneous, and chronically inflamed bowel. We call upon materials scientists, pharmaceutical scientists, immunologists, and gastroenterologists to move beyond acute-model proof-of-concept studies and embrace the complexity of human IBD. Journals, funding agencies, and regulatory bodies should incentivize studies that incorporate chronic model validation. The gap between acute models and chronic disease is not an abstract academic concern—it is the single most important barrier to clinical translation, and addressing it must become the central priority of the field. Only through multidisciplinary collaboration and rigorous, longitudinal safety validation can nanotherapies transition from promising concepts to transformative clinical realities.

In conclusion, IBD nanotherapy is at a critical inflection point, and the gap between bench innovation and bedside application remains wide. The next breakthrough will come not from incremental gains in targeting efficiency alone, but from redefining success—shifting the focus toward how nanotherapeutics interface with the dynamic, heterogeneous, and chronically inflamed bowel. We call upon materials scientists, pharmaceutical scientists, immunologists, and gastroenterologists to move beyond acute-model proof-of-concept studies and embrace the full complexity of human IBD. Journals, funding agencies, and regulatory bodies should actively incentivize studies that incorporate chronic model validation. The gap between acute models and chronic disease is not an abstract academic concern—it is arguably the most critical barrier to clinical translation, and prioritizing chronic disease validation in preclinical pipelines must become a central priority of the field. Only through multidisciplinary collaboration and long-term safety validation can nanotherapies evolve from promising concepts into transformative clinical realities.

Disclosure

The author(s) report no conflicts of interest in this work.