Pathogenesis guided application of nanozymes in the treatment of inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut that has caused an escalating burden on the global healthcare system in recent years. Researchers have been actively seeking innovative therapeutic strategies to combat this intractable disease. Recent advances in nanozyme technology have opened up new avenues for the development of novel therapeutic strategies for IBD. This review provides a comprehensive overview of the related works in the developments and applications of different nanozymes for IBD therapy. By overviewing the known pathogenesis of IBD and pathogenesis-guided applications of nanozymes in IBD therapy, this review highlights the opportunities for nanozyme-based strategies to address IBD via the underlying mechanisms. This review also examines the current state of nanozyme research in IBD, including the design and application of nanozymes, and discusses the challenges and future directions for this emerging field. In addition, by integrating the understanding of IBD pathogenesis with the development of nanozyme technology, this review aims to stimulate further research to uncover new opportunities for this debilitating disease.

Graphical abstract

1. Introduction

Inflammatory bowel disease (IBD), a chronic inflammatory gut disease that significantly impacts the quality of life for millions globally, has demonstrated an increasing burden on healthcare systems in recent years [1]. The IBD initially appeared only in developed countries, but its impact has been felt globally, garnering extensive attention internationally [2]. There are two main types of IBD: ulcerative colitis (UC) and Crohn's disease (CD). Both of them are illnesses with times of remission and relapse. The symptoms of IBD can vary significantly from one individual to another and are often specific to the particular type of IBD. UC is characterized by continuous inflammation and sores in the lining of the large intestine, leading to symptoms like diarrhea, abdominal pain, rectal bleeding, urgency, fatigue, and weight loss. Complications include toxic megacolon, colon cancer, osteoporosis, anemia, and an increased risk of other conditions [3,4]. CD, on the other hand, can affect any part of the digestive tract, causing patchy inflammation, irritation, and fistulas in the gut lining. Symptoms include diarrhea, abdominal pain, fatigue, weight loss, and rectal bleeding, with complications such as malnutrition, osteoporosis, anemia, additional fistulas, and an increased risk of colon cancer (Fig. 1) [5]. While both conditions share similar symptoms, CD tends to cause more widespread inflammation, abdominal pain, weight loss, and fatigue, whereas UC is more likely to cause rectal bleeding and urgency [6].

Fig. 1.

The introduction of the two main types of IBD: ulcerative colitis and Crohn's disease.

Although the exact mechanisms underlying IBD are still not fully understood, research suggests that it may involve the activation of immune cells, the production of pro-inflammatory cytokines, and the disruption of the gut epithelial barrier [[7], [8], [9]]. Additionally, the gut microbiota and overexpression of reactive oxygen species (ROS) is thought to play a crucial role in the development and progression of IBD. Current clinical treatments focus on symptom management, maintaining patients at a manageable level, and reducing the risk of recurrence [10,11]. While there have been advancements in IBD therapeutic options in recent years, conventional treatments primarily rely on pharmacotherapy, including aminosalicylates, corticosteroids, immunomodulators, and biologics, as well as surgery when necessary. However, the pharmacotherapy only provides temporary relief, and its long-term use is often associated with significant side effects. Broad-spectrum antibiotics could destroy harmful bacteria, but long-term administration increases the risk of antibiotic resistance [12,13]. The tumor necrosis factor (TNF) inhibitors and novel biologic drugs, has been a significant breakthrough, enabling long-term remission and modifying the disease course [14]. Moreover, owing to its chronic and incurable features, complete eradication of the disease remains elusive. Thus, there is a pressing need for safer and more effective treatments to address the challenges faced by many patients.

With advancements in nanotechnology research and the continuous progress of modern medical technology, it has been found that nanomaterials hold huge potential in the treatment of IBD [15,16]. Their unique properties, such as small size, high surface area, and ability to target specific cells and tissues, make them attractive candidates for the development of novel therapeutic strategies [[17], [18], [19]]. Among the nanomaterials, nanozymes, which are nanomaterials with enzyme-like characteristics, have been an attractive way to design catalytic systems for biological applications [[20], [21], [22]]. Researchers found that nanozymes can selectively target and degrade ROS to reduce the inflammation and oxidative stress in gut. Furthermore, nanozymes can also be designed to mimic the natural antioxidant enzymes found in the body, providing a more sustainable and long-term approach to managing IBD [23]. At present, there have been many studies on the implementation of specific nanozyme therapy for different pathogenic causes of IBD [24]. The pathogenesis guided strategy tailored nanozymes based on unique pathogenic factors to provide more personalized and effective treatments.

In this review, we aim to provide a comprehensive overview of the recent advances in the pathogenesis guided application of nanozymes in the treatment of IBD. We briefly overview the current known understanding of IBD pathogenesis, highlighting the key role of oxidative stress, inflammation, install barrier, and gut microbiota dysbiosis in the development and progression of the disease. Additionally, we also summarize the recent advances in the design and development of nanozymes for IBD treatment. The focus will be on highlighting the innovative applications of nanozymes and their promising role in addressing the challenges associated with different pathogenesis. Finally, we highlight the challenges and opportunities in the field, and provide perspectives on the future directions of nanozyme-based therapy for IBD. Through a comprehensive analysis, this review aims to shed light on the potential of nanozymes as a novel therapeutic approach for IBD. We hope to promote the innovative development of nanozymes in the medical field, offering patients better treatment choices and renewed hope.

2. The pathogenesis of IBD and the potential targets of nanozyme therapy

The pathogenesis of IBD is an extremely complex process. The main mechanisms involve excessive oxidative stress causing intestinal microenvironmental disorder and oxidative damage, which further develops into IBD [8]. Additionally, intestinal flora imbalances, necrosis of intestinal epithelial cells, and disruptions in the intestinal microenvironment may cause the damage of the intestinal barrier, leading to increased intestinal permeability. This section will detail the possible pathogenesis of IBD from several possible aspects: genetic factors, oxidative stress, endoplasmic reticulum (ER) stress, inflammatory cytokines, intestinal barrier damage, and gut microbiota disorder (Fig. 2).

Fig. 2.

Schematic representation of IBD pathogenesis. IBD risk genes listed at the bottom of oval panel disrupt key pathways in the gut, leading to inflammation and disease. The gut microbiota triggers immune responses, while the intestinal barrier maintains integrity through dynamic remodeling. Adaptive immunity induces antigen-specific responses, cytokine networks facilitate intercellular communication, and inflammation leads to tissue remodeling and fibrosis. Cellular stress responses adapt to stressors such as ER stress, oxidative stress, and hypoxia.

2.1. Genetic factors

Recent genome-wide searches have successfully identified multiple genes that contribute to the susceptibility of IBD [25]. Initial studies identified NOD2 as a susceptibility gene for CD [26,27], and subsequent research has confirmed several additional genes, including IBD5, IL23R, and ATG16L1 [28,29]. These genetic variants suggest that innate immunity, autophagy, and phagocytosis play critical roles in the development of CD. Notably, some genes associated with CD, such as IL23R and PTPN2, are also linked to UC or other autoimmune disorders, implying that a subset of IBD patients may share common triggers with these conditions. In addition, the genetic variation alone cannot fully explain the variability in disease presentation, including age at diagnosis, location, and complications. Furthermore, a large genotype-phenotype study has hinted at potential distinctions between ileal CD, colonic CD, and UC based on genetic risk factors [30]. However, current nanozymes cannot address IBD problems stemming from genetic issues. This limitation is attributed to the lack of gene editing capabilities of nanozyme, highlighting the need for further investigation in this area. Some promising strategies can be explored, such as the co-delivery of nanozymes and gene editing tools, like CRISPR-Cas9, via nanocarriers that target the site of inflammation. Alternatively, a sequential therapy approach can be explored, wherein nanozymes are initially utilized to mitigate oxidative stress and inflammation, followed by the application of gene editing technologies to rectify the genetic aberrations underlying IBD.

2.2. Oxidative stress

Oxidative stress is recognized as a significant contributor to the pathogenesis of IBD [31]. It plays a crucial role in disrupting the delicate balance of ROS and antioxidant defense mechanisms in the intestinal tissue. In the gastrointestinal tract, the sources of excessive ROS production are multifactorial and can contribute to oxidative stress in various ways. Endogenous ROS mainly comes from mitochondria, inflammatory cells, nitric oxide metabolism and oxidative enzymes, while the extraneous ROS mainly comes from intestinal environment and pathogenic bacteria. Excessive production of ROS, including superoxide anion, hydrogen peroxide, and hydroxyl radicals, increases oxidative stress between cells and tissues leading to oxidative damage [32]. The accumulation of oxidative damage to lipids, proteins, and DNA contributes to the cellular dysfunction and tissue injury [33]. This oxidative damage triggers inflammatory responses, perpetuates tissue injury, and further exacerbates the progression of IBD [34]. Oxidative stress is now a crucial therapeutic target for nanozymes in IBD treatment. The antioxidant capacity of nanozymes has been extensively validated, and their enzyme activity has been shown to effectively neutralize ROS and alleviate inflammation, making them an attractive therapeutic strategy for IBD treatment [35]. Moreover, the ROS-scavenging ability of nanozymes also forms the basis for their potential application in treating other pathologies. The combined treatment of multiple pathologies using nanozymes is an area that warrants further exploration, as it could lead to the development of more effective and efficient therapeutic strategies.

2.3. ER stress

Many studies show that the ER plays an important role in maintaining intestinal homeostasis. The ER is a cellular organelle responsible for protein folding, lipid metabolism, and calcium homeostasis [36]. When cells experience conditions that disrupt ER function, it can lead to the accumulation of unfolded proteins [37,38]. Accumulation of misfolded proteins within the ER lumen initiates the unfolded protein response (UPR). This is a cellular mechanism, aimed at restoring ER homeostasis [39,40]. The UPR encompasses distinct signaling pathways that vary in their downstream effects, promoting either cell survival or apoptosis. In IBD, chronic inflammation in the gastrointestinal tract can induce ER stress in intestinal epithelial cells, immune cells, and other resident cells [41]. ER stress is secondary to inflammation mediators or microbial factors may be a possible cause of destruction of intestinal epithelial cells. Thus, it is also a very potential therapeutic target for IBD therapy. Unfortunately, there are few nanozymes designed for targeting ER stress, and further research is warranted to fully explore the therapeutic potential of nanozymes in this context.

2.4. Inflammatory cytokines

Cytokines can be divided into pro-inflammatory and anti-inflammatory cytokines, the imbalance of which may lead to some inflammation in the body. Proinflammatory cytokines play an important role in the occurrence and development in the process of IBD. A prominent feature of IBD patients is the accumulation of inflammatory T cells and their proinflammatory factors in the gut [42]. In contrast, anti-inflammatory cytokines can inhibit inflammatory response and promote tissue repair. In IBD, the reduced secretion or dysfunction of anti-inflammatory cytokines may lead to the persistence and deterioration of intestinal inflammation [43]. Thus, the balance of pro-and anti-inflammatory cytokines is important for the pathogenesis of IBD. With the progress of the field, researchers have found that the regulation of inflammatory factors has gradually become another major target for the treatment of IBD with nano-zymes. Thus, inhibiting the expression or regulating the balance between pro-and anti-inflammatory cytokines should be a promising strategy for IBD therapy.

2.5. Immunity response

The immune response also plays a central role in the development and perpetuation of inflammation in IBD [44]. Mucosal B cells produce secretory immunoglobulin A (IgA) and immunoglobulin G (IgG), while T cells exhibit a diverse range of phenotypes, including Th1, Th2, and Th17 [45]. Besides, macrophages are important components in the innate immune response. These cells are responsible for recognizing and eliminating pathogens. They play a crucial role in the development and perpetuation of inflammation in IBD [46]. There are two main subsets of macrophages: M1 (classically activated) macrophages, which produce pro-inflammatory cytokines and contribute to chronic inflammation, and M2 (alternatively activated) macrophages, which produce anti-inflammatory cytokines and promote tissue repair [47]. As macrophages play a crucial role in IBD pathogenesis, modulating their polarization and enhancing their phagocytic function via nanozyme materials can have a significant impact on IBD treatment. Nanozymes can modulating the polarization of macrophages, shifting them from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype, which can help reduce inflammation and promote tissue repair and further research is warranted to fully explore the potential of this approach [48].

2.6. The intestinal barrier

The intestinal barrier is composed of multiple components that work together to maintain gut integrity and regulate the transport of substances. It consists of epithelial cells tightly joined by specialized intercellular junctions [49]. Additionally, the intestinal barrier includes a layer of mucus secreted by goblet cells, which acts as a lubricant and traps potential pathogens and toxins [50]. Furthermore, immune cells, such as specialized lymphocytes and antigen-presenting cells, are strategically located in the intestinal barrier. They monitor the gut environment, detect foreign antigens, and initiate immune responses when necessary. Together, these components form the intricate intestinal barrier, which plays a critical role in preventing the entry of harmful substances while allowing selective absorption of nutrients and maintaining immune homeostasis in the gut [51]. However, the intestinal barrier is susceptible to destruction by pathogens and exogenous substances, leading to some intestinal barrier damage. Consequently, restoring and maintaining a robust and functional intestinal barrier is a crucial aspect of IBD therapy, and nanozymes have the potential to play in achieving this goal. By targeting the intestinal barrier, nanozymes can help restore the integrity of the epithelial layer, enhance the expression and function of tight junction proteins, and promote the production of a healthy mucus layer. This, in turn, can help prevent the translocation of luminal antigens and toxins, reduce inflammation, and promote the resolution of inflammation.

2.7. Gut microbiota dysbiosis

There is a broad scientific consensus regarding the association between IBD and gut microbiota dysbiosis [52]. Numerous studies have consistently demonstrated significant alterations in the composition and function of the gut microbiota in individuals with IBD. The dysbiosis observed in IBD patients includes changes in the abundance, diversity, and relative proportions of specific bacterial species [53]. Intestinal homeostasis is largely altered by IBD-associated immune dysfunction and mucosal inflammation, which affect gut microbial composition, function [54]. Nanozymes have emerged as a promising tool for overcoming gut microbiota dysbiosis in IBD therapy. The nanozymes, with their antioxidant and proteolytic activities, can modulate the gut microbiota composition. By restoring the balance of the gut microbiota, nanozymes can help alleviate IBD symptoms, reduce inflammation, and promote the resolution of inflammation. These findings highlight the complex interplay between the gut microbiota and host factors in the development and therapy of IBD [55].

3. Nanozymes in IBD

Nanozymes are synthetic nanomaterials that possess intrinsic enzyme-like activities. Since the first discovery of the Fe₃O₄ nanozyme by Yan's group, the field of nanozymes has rapidly expanded [56]. Following this pioneering discovery, researchers worldwide have been actively investigating and developing nanozymes with diverse compositions, structures, and catalytic activities [[57], [58], [59], [60], [61], [62], [63]]. Subsequently, more and more materials are found to have enzyme analog activities, including oxidase-like (OXD-llike), peroxidase-like (POD-like), catalase-like (CAT-like), superoxide dismutase-like (SOD-like), glutathione peroxidase-like (GPx-like) properties and so on (Fig. 3) [[64], [65], [66], [67]]. Nanozymes can be designed with precise control over their size, shape, and surface properties, allowing for improved catalytic performance and tunability. They are generally more stable, cost-effective, and easier to synthesize in large quantities [68]. Additionally, they can be engineered to withstand harsh environmental conditions, making them suitable for a range of applications across various fields, including medicine, environmental science, and energy [69]. As the ROS is considered an important mediator in the pathogenesis of IBD, and therapeutic strategies targeting ROS are important for reducing the symptoms and progression of IBD.

Fig. 3.

Schematic representation of the common biological enzyme-like activity of nanozymes and the pathogenic targets applied in IBD therapy via nanozyme medicines. Nanozymes with GPx, SOD, and CAT mimic activity are commonly employed to alleviate oxidative stress, whereas those with POD and OXD activity are often utilized for their antibacterial properties.

Nanozymes, especially CAT-like, SOD-like, and GPx-like nanozymes, have been explored as a novel therapeutic approach for IBD. These nanozymes mimic the activity of natural enzymes, scavenging ROS, reducing oxidative stress and inflammation, and protecting the gut epithelium from damage [70]. CAT-like nanozymes, such as Pt nanoparticles, protecting cells against oxidative stress by catalyzing the breakdown of hydrogen peroxide (H₂O₂) into water (H₂O) and molecular oxygen (O₂) [71]. SOD-like nanozymes, such as cerium oxide nanoparticles, reduce oxidative stress catalyzes the ambiguity of superoxide radicals (O₂^•−) to H₂O₂ and O₂ [72]. GPx-like nanozymes, such as V₂O₅, reduce H₂O₂ and organic hydroperoxides using glutathione (GSH) as a cofactor (Fig. 3) [73]. POD-liked and OXD-like nanozymes exhibited redox-mediated ROS scavenging activity with the assistance of a reduced substrate [74]. Thus far, various nanozymes exhibiting antioxidant activity have been reported. Their enzyme-like activity levels have been thoroughly studied, and their functional sites have been identified through methods like density functional theory or chemistry experiments. These nanozymes offer a promising therapeutic approach for IBD, and further research is needed to fully understand their mechanisms of action and to develop them for clinical use.

Initially, nanozymes were simply used to reduce ROS in IBD. With continuous development, the functions of nanozymes have been continuously enriched, and they can simultaneously deal with multiple pathogenic factors of IBD in the same system. Now, nanozymes can not only scavenge ROS, but also modulate the immune response, inhibit pro-inflammatory cytokine production, and promote the production of anti-inflammatory cytokines. Nanozymes can also target specific cells or tissues, such as macrophages or the gut epithelium, to reduce inflammation and oxidative stress. Additionally, nanozymes can be designed to have sustained release properties, allowing for prolonged therapeutic effects. Overall, the evolution of nanozymes has transformed them into a powerful tool for the treatment of IBD, offering a multi-faceted approach to combat the complex pathophysiology of the disease.

4. Progress of nanozyme based therapy for IBD

Researchers have made significant progress in the development of nanozymes as therapeutic agents for IBD therapy. Various nanozyme have been constructed for different pathogenesis of IBD. Several studies demonstrate their potential to alleviate oxidative stress and inflammation in the gut. Notably, nanozymes also have shown promise in modulating inflammatory cytokines, improving intestinal barrier function, and promoting the growth of beneficial gut microbiota. Furthermore, nanozymes have been found to be well-tolerated and non-toxic, making them an attractive alternative to conventional treatments. While challenges remain, the progress made in nanozyme-based therapy for IBD is encouraging, and ongoing research is expected to further elucidate their therapeutic potential.

4.1. Initial stage: single antioxidant targeting

In the initial stage, nanozymes were designed to target excessive ROS and alleviate oxidative stress, which is a primary pathogenic factor. The core goal was to remove ROS and prevent oxidative damage to the gut mucosa [34]. Researchers developed nanozymes with antioxidant properties, such as SOD and CAT mimics, to neutralize oxidative stress. The excellent ROS scavenging capability of nanozymes has been proved by many researchers. For examples, Mugesh et al. successfully proved the cytoprotective potential of V₂O₅ nanozyme [75] and Huang et al. even utilized the multi-nanozymes self-assemble platform to mimic an intracellular antioxidant system [76]. Therefore, the ability of nanozymes to regulate ROS levels and maintain a favorable redox environment can help alleviate oxidative stress-associated damage and promote the resolution of inflammation in many disease models.

Earlier, in order to alleviate excessive oxidative stress in IBD, researchers introduced nanozymes into the treatment of IBD. The first paper was provided by Chen's group, they constructed poly(vinylpyrrolidone)-modified Prussian blue (PPB) nanoparticles to reduce colitis in mice (Fig. 4A) [77]. This work demonstrated the protective effect of PB-based nanozymes against IBD in vivo. Although this study primarily explores the POD activity for ROS elimination, it is noteworthy that POD enzymes can paradoxically generate additional oxidative stress by producing free radical intermediates during substrate reduction. To avoid this limitation, the same group constructed a manganese Prussian blue nanozymes (MPBZs) complex nanozyme with multi-enzyme activity for IBD therapy (Fig. 4B). Owing to their low redox potential and abundant variable valence states, MPBZs showed excellent CAT-like and SOD-like activity for ROS elimination. Besides, the designed MPBZs preferentially accumulate at inflamed mucosa with positively charged artificial surfaces in dextran sulfate sodium (DSS) induced colitis mice via size/charge-mediated inflammation-targeting strategies [78].

Fig. 4.

(A) Schematic illustration of synthesis step of PPBs for DSS induced colitis therapy. Adapted with permission from Ref. [77] Copyright 2018 American Chemical Society. (B) Schematic illustration of the MPBZs for IBD therapy. Adapted with permission from Ref. [78] Copyright 2019 Ivyspring International Publisher. (C) The Pt@PCN222-Mn nanozyme was designed by e integrating a Mn-based metal-organic framework (MOF) and platinum nanoparticles (Pt NPs). Adapted with permission from Ref. [79] Copyright 2020 AAAS publications. (D) Representation of CeO₂@MMT fabrication and a promising orally administered therapeutic strategy for IBD. Reprinted with permission from Ref. [80] Copyright 2020 Wiley-VCH GmbH.

At the same period Wei's group also developed an integrated cascade nanozyme, Pt@PCN222-Mn simulating the biological antioxidant system (Fig. 4C). The nanozyme mimics the functions of SOD and CAT enzyme by integrating a Mn-based metal-organic framework (MOF) and platinum nanoparticles (Pt NPs) [79]. The Mn-MOF transforms oxygen radicals into hydrogen peroxide, while the Pt NPs catalyze the decomposition of hydrogen peroxide into water and oxygen, mimicking the cascade catalytic reaction systems of SOD and CAT in living organisms. However, due to the limitations of the administration method of Mn-MOF, they further explored an orally administered nanozyme, CeO₂@Montmorillonite (CeO₂@MMT) for the application [80]. The CeO₂ NPs are in situ grown onto MMT sheets, forming a stable complex that can be orally delivered to the stomach, target inflamed colon tissue through electrostatic interactions, and scavenge ROS to reduce inflammation without significant systemic exposure. (Fig. 4D).

With the early exploration of nanozyme in IBD therapy, more and more researches constructed various nanozymes for ROS relief in IBD therapy, such as, Mn₃O₄ [[81], [82], [83]], polyoxometalate [84], Mo₃Se₄ [85], C dots [86], Co nanosheets [87], Mo nanodots [88], MOF [[89], [90], [91], [92]], etc. [[93], [94], [95], [96], [97], [98], [99], [100]] In addition, recent studies have increasingly emphasized the additional functions given to nanozyme, which can effectively remove ROS and relieve oxidative stress, but also deal with other pathogenic factors of IBD, such as, modulating the inflammatory cytokines, balancing immunity response, gut microbiota and etc., indicating the huge potential for nanozyme to IBD therapy.

4.2. Functional expansion stage: inflammation factors and immune regulation

In the functional expansion stage, researchers began to explore the potential of nanozymes to target pro-inflammatory factors and immune cell polarization. This breakthrough direction was driven by the recognition that IBD is a complex disease characterized by chronic inflammation and immune dysregulation. Researchers developed nanozymes that could target specific pro-inflammatory cytokines, such as TNF-α and IL-1β, and modulate immune cell polarization, promoting a more balanced immune response. This approach showed greater therapeutic potential than antioxidant targeting alone, as it addressed the underlying inflammatory and immune mechanisms driving IBD. By targeting the imbalanced inflammatory cytokine profile in IBD, nanozymes further show their multifunctional potential tool for the treatment of this complex disease.

4.2.1. Inflammation factors

Initially, researchers focused on neutralizing pro-inflammatory cytokines such as TNF-α and IL-1β, which are key drivers of inflammation in IBD. By developing nanozymes that could specifically target these cytokines, researchers demonstrated the potential to reduce inflammation and alleviate IBD symptoms. Wei's group and Sun's group created metal-based nanozymes to regulate inflammatory factors respectively. A valence-engineered self-cascading antioxidant nanozyme, LiMn₂O₄ (LM), designed by Wei's group [99]. The optimized nanozyme demonstrated enhanced SOD, CAT, and GPx-like activities, along with the ability to scavenge hydroxyl radicals (Fig. 5A). Besides, the nanozymes could effectively down-regulated the pro-inflammatory factor TNF-α and upregulated the anti-inflammatory factor IL-10 showing improved antioxidant and therapeutic effects at the cellular level and in an IBD model. Sun and his coworkers constructed nanoprobiotics by encapsulating manganese dioxide (MnO₂) nanozymes within probiotic-derived outer membrane vesicles (OMVs) [101]. Combined with the anti-inflammatory drug metformin, this nanoprobiotics rebuild pro-inflammatory microenvironment and regulated the inflammatory cytokine successfully (Fig. 5B). This research presents a safe and effective bionanoplatform for the treatment of inflammation-mediated intestinal diseases, potentially offering a new approach to IBD management.

Fig. 5.

(A) Schematic illustration of a valence-engineered self-cascading antioxidant nanozyme, LiMn₂O₄ (LM), designed to target and treat IBD. Adapted with permission from Ref. [99] Copyright 2022 Wiley-VCH GmbH. (B) Schematic illustration of the Nanoprobiotics by encapsulating manganese dioxide (MnO₂) nanozymes within probiotic-derived outer membrane vesicles (OMVs) for IBD therapy. Adapted with permission from Ref. [101] Copyright 2023 American Chemical Society. (C) The development and application of oral carbon dot nanozymes (C-dots) for the management of UC. Adapted with permission from Ref. [102] Copyright 2024 Elsevier Ltd. (D) Representation of PPy/PFD@Inulin gel, for the simultaneous treatment of IBD and its fibrotic complications. Reprinted with permission from Ref. [103] Copyright 2024 Nature Research.

In addition, non-metal nanozymes have also been studied. Ma et al. presented the development and application of oral carbon dot nanozymes (C-dots) with red fluorescence and SOD-like activity for the management of UC [102]. The C-dots, synthesized from glutathione and biotin, were shown to eliminate excess ROS, protect cells from oxidative stress, and reduce the expression of pro-inflammatory cytokines both in vitro and in vivo (Fig. 5C). Another example was developed by Zha's group. The PPy/PFD@Inulin gel was integrated polypyrrole (PPy) nanozyme and the antifibrotic drug pirfenidone (PFD) in inulin gel (Fig. 5D) [103]. The hydrogel extends the gastrointestinal residence time of PPy nanozymes and PFD, enabling efficient reduction of pro-inflammatory cytokines, enhancement of intestinal epithelial barrier repair, and suppression of intestinal fibrosis through sustained reactive oxygen and nitrogen species scavenging.

4.2.2. Immune regulation

Subsequently, some researchers focused their target to immune regulation. The core concept is exploring the potential of nanozymes to modulate immune cell polarization and promote a more balanced immune response. Especially, the macrophage and NLRP3 inflammasome have been targeted by nanozymes, which can polarize macrophages towards an anti-inflammatory phenotype. Moreover, nanozymes have been designed to inhibit the NLRP3 inflammasome, thereby reducing the production of IL-1β and IL-18, and alleviating inflammation and tissue damage. For example, Qin et al. presented a mucoadhesive probiotic-based oral microcarrier, BL@HABN, for the treatment of IBD (Fig. 6A) [104]. The microcarrier combines Bifidobacterium longum (BL), a probiotic bacterium, with hyaluronic acid-bilirubin nanomedicine (HABN) to modulate intestinal inflammation and type 2 macrophage (M2) differentiation. Besides, biomimetic strategies are also used in the construction of nanozymes. Wang et al. developed an innovative oral drug delivery system via M2 macrophage membrane-coated Janus nanomotors embedded in sodium alginate microspheres (Motor@M2M@SAM) [105]. The system leverages the M2 macrophage membrane's ability to neutralize inflammatory cytokines and target inflamed tissues, while the Janus nanomotors generate oxygen bubbles to propel the system across the mucus barrier into inflamed colon tissues (Fig. 6B). The Motor@M2M@SAM system demonstrated effective ROS scavenging, macrophage reprogramming capability in both in vitro and in vivo experiments.

Fig. 6.

Schematic illustration of a mucoadhesive probiotic-based oral microcarrier, BL@HABN, for the treatment of IBD. Adapted with permission from Ref. [104] Copyright 2023 Elsevier Ltd. (B) Schematic illustration of the M2 macrophage membrane-coated Janus nanomotors embedded in sodium alginate microspheres (Motor@M2M@SAM). Adapted with permission from Ref. [105] Copyright 2024 AAAS publications. (C) The development and application of 2D cobalt oxyhydroxide nanosheets (Co NSs) as a novel nanozyme for the management of ulcerative colitis (UC). Adapted with permission from Ref. [87] Copyright 2023 Wiley-VCH GmbH. (D) Representation of an oral nano-antioxidant, Ce-Cur@MCS, by encapsulating nanoceria (CeO₂) and curcumin (Cur) within mannose-modified chitosan (MCS). Reprinted with permission from Ref. [106] Copyright 2023 Elsevier Ltd.

Nanozymes with metal active centers can also play corresponding functions. Zhang et al. study constructed 2D cobalt oxyhydroxide nanosheets (Co NSs) as a novel nanozyme with multienzyme-like activities, including POD, CAT, and SOD, which exhibit superior ROS scavenging properties (Fig. 6C) [87]. The research reveals that Co NSs can inhibit NLRP3 inflammasome activation by targeting ROS, thereby attenuating inflammation in both LPS induced systemic inflammation and DSS induced colitis mouse models. Ren et al. introduced an oral nano-antioxidant, Ce-Cur@MCS, for targeted treatment of IBD by encapsulating nanoceria (CeO₂) and curcumin (Cur) within mannose-modified chitosan (MCS) [106]. The nano-antioxidant specifically delivers to colonic inflammation sites, particularly macrophages, mimicking SOD and CAT to eliminate ROS and scavenge hydroxyl radicals (Fig. 6D). It modulates macrophage polarization by reducing M1 and enhancing M2 phenotypes, and increases the expression of GPX4 to protect intestinal cells from ferroptosis. Accumulating evidence from numerous studies has consistently demonstrated that modulating the immune response is a promising therapeutic target for IBD treatment, and ongoing research continues to explore and refine this approach.

4.3. Multi-target synergy stage: barrier repair and microbiome remodeling

In the multi-target synergy stage, researchers integrated multiple functionalities into nanozymes to synchronously repair physical barriers and regulate microecology. This integration strategy recognized that IBD is characterized by a breakdown of the gut mucosal barrier, allowing toxins and antigens to penetrate the mucosa and trigger inflammation. Additionally, the gut microbiome plays a critical role in IBD pathogenesis. Researchers developed nanozymes that could repair and restore the gut mucosal barrier, while also regulating the gut microbiome, promoting a healthy microbiota. This approach has shown promising results in preclinical studies, demonstrating that multi-target nanozymes can achieve more comprehensive therapeutic benefits than single-target approaches.

4.3.1. Barrier repair

As the intestinal barrier damage is an important pathogenesis in IBD, nanozyme therapy has been expanded to target the restoration of the intestinal epithelial barrier function. Nanozymes have been designed to promote the expression of tight junction proteins, and reduce the permeability of the intestinal epithelial layer. Additionally, nanozymes have been shown to enhance the recovery of intestinal mucosal barrier, promoting the repair of damaged tissues. By targeting the restoration of the intestinal epithelial barrier function, a typical Se nanozyme was developed by Hu's group (Fig. 7A) [107]. The SP@CS-SeNPs system demonstrated significant anti-inflammatory effects and improved the expression of tight junction proteins. The results showed significantly increased the expression of Occludin, Claudin-1, and ZO-1 in the colon, which proved the repaired the damaged intestinal barrier in a colitis mice model. Besides, a metal polyphenol network/cerium oxide artificial enzyme nanoplatform (MPN@CeO_x) was developed for the management of intestinal inflammation (Fig. 7B) [108]. The nanoplatform's H₂O₂-responsive release of Fe³⁺ and Ce elements enables MRI/CT imaging of UC, and oral administration of enteric-coated MPN@CeO_x in mice colitis models alleviates intestinal inflammation and barrier dysfunction. RNA sequencing analysis reveals that MPN@CeO_x ameliorates UC symptoms primarily through inflammation-related signaling pathways, demonstrating its potential as an innovative diagnosis and treatment approach for UC.

Fig. 7.

Schematic illustration of a an orally deliverable microalgal-based carrier system, SP@CS-SeNPs, for the treatment of IBD. Adapted with permission from Ref. [107] Copyright 2024 American Chemical Society. (B) Schematic illustration of a metal polyphenol network/cerium oxide artificial enzyme nanoplatform (MPN@CeO_x) for the management of intestinal inflammation. Adapted with permission from Ref. [108] Copyright 2023 Elsevier Ltd. (C) The development of macrophage-biomimetic liposomes (C-dots@Lipo-M) for deliverying carbon dot nanozymes (C-dots). Adapted with permission from Ref. [109] Copyright 2023 Elsevier Ltd. (D) Representation of platelet-inspired nanomedicine (PM@Pic/PtCD@NP) for the treatment of ulcerative colitis (UC). Reprinted with permission from Ref. [110] Copyright 2024 Elsevier Ltd.

In addition, two kinds of biomimetic liposomes showed great therapeutic effect in intestinal barrier restoration and remission of IBD. The macrophage-biomimetic liposomes (C-dots@Lipo-M) combined with C-dots possess SOD-like activity, effectively clearing ROS and alleviating inflammation (Fig. 7C) [109]. In DSS induced UC models, C-dots@Lipo-M demonstrated satisfactory preventive and therapeutic effects by reversing shortened colon length, scavenging ROS, decreasing pro-inflammatory cytokines, and reducing barrier protein expression at colon sites. What's more, the platelet-inspired nanomedicine (PM@Pic/PtCD@NP) showed enhanced capability to hitchhike on neutrophils to the inflammation site (Fig. 7D) [110]. Intravenous administration of PM@Pic/PtCD@NP in a murine model of colitis resulted in partial reversal and prevention of intestinal inflammation and recover the intestinal barrier. The related researchers provided a new targeted strategy to improve nanozymes therapeutic efficiency and extend their biomedical applications in inflammation-related diseases.

4.3.2. Modulation of gut microbiota

In IBD, a dysbiosis of the gut microbiota has been implicated as a key pathogenic factor [111]. The alterations in the composition and function of the microbiota contributing to chronic inflammation and tissue damage. Moreover, nanozymes have also been explored to targeting the gut microbiota in this stage. The nanozymes could inhibit the growth of pathogenic bacteria and promote the growth of beneficial microorganisms. Therefore, they could restore intestinal flora diversity, reestablishing a healthy gut microbiota and alleviating IBD symptoms. This modulation of the gut microbiota could lead to a reduction in inflammation, improved epithelial barrier function, and enhanced immune homeostasis, ultimately contributing to the remission of IBD. Wang et al. presented the synthesis and application of histidine-derived carbon dots (His-CDs) as a nanomedicine for the treatment of IBD (Fig. 8A) [112]. This work demonstrate that His-CDs possess strong antioxidant and multi-enzyme activities, which could reduce oxidative stress damage in cells and animals, regulate the redox balance, and restore the gut microbiota composition in colitis-induced mice. Furthermore, fecal microbiota transplantation experiments confirm that the beneficial bacteria enhanced by His-CDs can effectively alleviate DSS induced colitis [113]. Another work dexterously modified the nanozyme medicine with a yeast cell wall (YCW) to enhances it colonization ability. Chen et al. created a zinc-doped Prussian blue analogue (ZnPBA) nanozyme with a yeast cell wall (YCW) exterior (Fig. 8B) [114]. The ZnPBA nanozyme demonstrates significant capability in restoring redox homeostasis by scavenging ROS and inhibiting the NF-κB signaling pathway. Moreover, ZnPBA@YCW effectively regulates the gut microbiota by increasing bacterial richness and diversity, promoting probiotics, and reducing pathogenic E. coli levels.

Fig. 8.

Schematic illustration of synthesis and application of histidine-derived carbon dots (His-CDs) as a nanomedicine for the treatment of IBD. Adapted with permission from Ref. [112] Copyright 2024 Elsevier Ltd. (B) Representation of a yeast cell wall (YCW) exterior and encapsulates a zinc-doped Prussian blue analogue (ZnPBA) nanozyme for the treatment of ulcerative colitis (UC). Reprinted with permission from Ref. [114] Copyright 2024 Elsevier Ltd. (C) Artificial-enzyme-modified Bifidobacterium longum (BL) probiotics, designated as BL@B-SA₅₀, for the treatment of IBD. Adapted with permission from Ref. [115] Copyright 2023 Nature Research. (D) Schematic illustration of a modified prebiotic-based "shield" armed probiotic system, Fe-TA@mGN for the management of intestinal inflammation. Adapted with permission from Ref. [116] Copyright 2023 American Chemical Society. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

The probiotics are also used to construct nanozyme complexes for IBD treatment, especially for the regulation of the gut microbiota. Cao et al. introduced the artificial-enzyme-modified Bifidobacterium longum (BL) probiotics, designated as BL@B-SA50, for the treatment of IBD (Fig. 8C) [115]. The study leverages biocompatible artificial enzymes with SOD and CAT-like activity to mimic natural antioxidant defense systems, effectively scavenging ROS and reducing inflammation. The engineered probiotics not only persist in the harsh gastrointestinal environment but also enhance the viability of BL, facilitating the reshaping of intestinal barrier functions and restoration of gut microbiota. Similarly, Wan et al. constructed a modified prebiotic-based "shield" armed probiotic system, Fe-TA@mGN, designed to enhance the resistance of Escherichia coli Nissle 1917 (EcN) to gastrointestinal stresses and prolong its intestinal retention for the synergistic alleviation of DSS induced colitis (Fig. 8D) [116]. The "shield" is composed of an Fe³⁺-tannic acid cross-linking network and carboxymethylated β-glucan (mGN), which not only improves EcN's survival rate but also promotes intestinal colonization. The nanozyme synergized with EcN could alleviate colitis by modulating gut microbiota and promoting short-chain fatty acids production. This strategy of using modified prebiotics to arm probiotics offers a promising approach for the effective alleviation of IBD.

5. Conclusions and perspectives

The field of nanozyme therapy for IBD has witnessed remarkable progress and demonstrated significant potential for improving treatment outcomes. We summarize the recently published typical research work for nanozyme in IBD therapy (Table 1). The integration of nanozymes with specific targeting capabilities allows for precise control over their therapeutic behavior, enabling targeted and controlled interactions with specific molecular targets. Additionally, the biocompatibility of nanozymes ensures their compatibility with complex biological systems, minimizing unwanted side effects and improving treatment safety. While nanozyme therapy has shown great promise in the treatment of IBD, there are several limitations that need to be addressed before it can be translated into clinical practice.

• (1)Ambiguous molecular biological mechanisms: At present, in the treatment of IBD with nanozymes, only the ROS clearance mechanism is relatively clear, and the mechanisms of other pathogeneses are completely unknown [161]. In many cases, it is believed to be a collateral result of ROS clearance. This limited understanding of the mechanisms underlying nanozyme therapy for IBD hinders the development of more effective and targeted treatments. Elucidating the molecular mechanisms of nanozyme therapy in IBD is crucial for optimizing their design, efficacy and delivery, ultimately enhancing their therapeutic potential. Therefore, further research is warranted to uncover the complex interactions between nanozymes and the gut microbiota, immune system, and epithelial cells, as well as to explore the potential of nanozymes in modulating other factors.
• (2)Combination therapies: Currently, nanozyme treatment methods are relatively simple, relying on the enzymatic activity of the nanozyme to alleviate IBD symptoms. However, the complex pathophysiology of IBD suggests that a single-modality approach may not be sufficient to achieve optimal therapeutic outcomes. In the future, if combining nanozymes with other therapeutic agents, such as biologics, small molecules, probiotics, or anti-inflammatory agents, it may offer a more effective and comprehensive approach to IBD management [162]. By leveraging the synergistic effects of multiple agents, combination therapy has the potential to enhance the therapeutic efficacy of nanozymes [[163], [164], [165]].
• (3)Metabolic pathways and long-term safety: Although current studies on the use of nanozymes in the treatment of IBD have all stated that the nanozyme system has good biocompatibility, the metabolic pathways and long-term safety of nanozymes have received relatively little attention. For instance, the metabolism of nanozymes can influence their half-life, biodistribution, and clearance rates. Moreover, the metabolic products of nanozymes can also influence their long-term safety [166]. In our view, longitudinal studies are essential to assess the potential risks associated with prolonged exposure to these nanomaterials. We believe that a deeper understanding of the metabolic pathways of nanozymes is essential to optimize their design and delivery. The long-term consequences of nanozyme administration are needed for further investigation to ensure their safe and effective translation to clinical practice [167].
• (4)Lack of specificity: Currently, major nanozymes used in IBD treatments lack the specificity. Although some nanozymes have been endowed with certain targeting capabilities, they are usually designed to target oxidative stress and inflammation. Few nanozymes possess the ability to specifically target the inflamed areas of the gut or the underlying causes of IBD [168]. In our opinions, the lack of specificity in nanozyme-based IBD therapy is largely due to non-selective uptake, limited targeting capabilities, and the complexity of the gut microenvironment. Engineering nanozymes with enhanced targeting capabilities is believed to enable their selective accumulation at inflammation sites, thereby amplifying therapeutic efficacy while minimizing off-target effects. This approach could ultimately pave the way for improved safety profiles and more personalized treatment.
• (5)Potential immune response: It is alarming that the potential immune responses of nanozymes have been understudied, even though immune responses can significantly impact the safety and efficacy of nanozyme therapy. As we know, the immune system is highly complex and can respond to nanozymes in various ways, such as by recognizing them as foreign substances, triggering inflammation, or activating immune cells. If not properly addressed, these immune responses can result in unintended consequences, including immune-related adverse reactions. Thus, we believe that a thorough understanding of the immune responses of nanozymes is crucial to ensure their safe and effective translation to clinical practice. Therefore, it is essential to investigate the immunogenic potential of nanozymes, identify the immune cells and pathways involved, and develop strategies to mitigate any adverse immune responses in future.

Table 1.

Summary of the nanozymes applied in IBD therapy.

Enzyme-like activity	Nanozyme	Active ingredient	Activity	Model	Administration	Pathogenetic targets	Ref.
Single enzyme Activity
CAT	Mn-MOF microcapsules	Mn-MOF	CAT	UC	Oral	ROS	[89]
	SiRNA-GBSA(CHI/TA)n NPs	GAGQOD	CAT	UC	Oral	ROS, inflammatory cytokines, macrophage polarization, intestinal barrier, gut microbiota, gut microbiota-brain interactions	[117]
	ICANs	CeNPs	CAT	UC	Oral	ROS, inflammatory cytokines, intestinal barrier,	[118]
	EcN-Fh@F	FhNPs	CAT	UC	Oral	ROS, inflammatory cytokines, macrophage polarization, neutrophil infiltetion, intestinal barrier, gut microbiota	[119]
SOD	CCZM	C-Dot	SOD	UC	Oral	ROS, CD98, inflammatory cytokines	[86]
	C-dots@Lipo-M	C-dots	SOD	UC	I.V.	ROS, inflammatory cytokines, intestinal barrier	[109]
	MPN@CeOx	CeOx	SOD	UC	Oral	ROS, inflammatory cytokines, intestinal barrier	[108]
	MeNPs	melanin	SOD	UC	Oral	ROS, Endoplasmic reticulum (ER) stress, inflammatory cytokines, macrophage polarization, intestinal epithelial cell apoptosis, intestinal barrier, gut microbiota	[95]
	CeO2@S100	CeO2	SOD	UC	Oral	ROS, inflammatory cytokines, intestinal barrier, gut microbiota	[120]
	Carbon dot NPs	C Dots	SOD	UC	Oral	ROS, inflammatory cytokines, gut microbiota	[102]
	CF@EM	Cur-Fe	SOD	UC	Oral	ROS, inflammatory cytokines, macrophage polarization, intestinal barrier, gut microbiota	[121]
	HZn-TA NPs	HZn-TA	SOD	UC	Oral	ROS, RNS, inflammatory cytokines, intestinal barrier	[122]
	CeO2/spores	CeO2	SOD	Acute gastroenteritis	Oral	ROS, S. Typhimurium, gut microbiota	[123]
	GH-CDs	C Dots	SOD	UC	Oral	ROS, RNS, inflammatory cytokines, intestinal epithelial barrier, gut microbiota	[124]
	Zein/CR/CeO2	CeO2	SOD	UC	Oral	ROS, inflammatory cytokines, macrophage polarization, intestinal epithelial barrier, gut microbiota	[125]
	DZ@YM	DHM-Zn	SOD	UC	Oral	ROS, inflammatory cytokines, gut microbiota	[126]
GPx	MIL-47(V)-NH2 MOF	V	GPx	UC	Oral	ROS, macrophages polarization, downregulate IL-6, IL-1β, TNF-α, and iNOS, upregulate IL-10, IL-4, Arg-1	[127]
DNase-I	DNase-NZ	DNase-I	DNase-I	UC	Rectal administration	neutrophil extracellular traps (NETs)	[128]
Antioxidant	HfS2@TA	HfS2	ORS	UC	Oral	ROS, RNS, inflammatory cytokines	[129]
	LBL-CO@MPDA	PDA	ORS	UC	Oral	ROS, inflammatory cytokines, p38 MAPK and NF-κB (p50/p65) signaling pathways, inflammatory cytokines, intestinal barrier	[130]
	Fe-TA@mGN	Fe-TA	ORS	UC	Oral	ROS, inflammatory cytokines, intestinal barrier, gut microbiota	[116]
	BL@HABN	HABN	ORS	UC	Oral	ROS, inflammatory cytokines, macrophage polarization, intestinal barrier, gut microbiota	[104]
	Cu2(Olsa)/Gel	Cu2(Olsa)	ORS	UC&CD	Oral	ROS, inflammatory cytokines, intestinal barrier, gut microbiota	[131]
	EcN@SA-pBDT-TA	pBDT-TA NPs	Antioxidant	UC	Oral	ROS, inflammatory cytokines, macrophage polarization, intestinal barrier, gut microbiota	[132]
	EcN@PC–Fe/HA	Fe-TA	Antioxidant	UC	Oral	ROS, inflammatory cytokines, macrophage polarization, T cell differentiation, intestinal barrier, gut microbiota	[133]
Double enzyme activity
CAT, SOD	MPBZ	PB, Mn2+	CAT, SOD	UC	Oral	ROS	[78]
	Pt@PCN222-Mn	TCPP-Mn, Pt	CAT, SOD	UC & CD	I.P.	ROS	[79]
	CeO2@MMT	CeO2	CAT, SOD	UC	Oral	ROS	[80]
	Mn3O4@OA@PEG NPs	Mn3O4	CAT, SOD	UC & CD	I.P.	ROS	[81]
	SC/WCC	enzyme	CAT, SOD	UC	Oral	ROS, downregulate IL-6, TNF-α	[134]
	CeNP-PEG	CeNP	CAT, SOD	UC	Oral	ROS, macrophages polarization, Th1/Th17 response	[135]
	CCNZ	CeO2	CAT, SOD	UC	Oral	ROS	[136]
	CeO2 NPs@metal	CeO2, Au,Pt,Ag	CAT, SOD	UC	I.P.	ROS	[137]
	ZVMNs	molybdenum nanodots	CAT, SOD	UC	Oral	ROS, inflammatory cytokines, NF-кB pathway	[88]
	MPDB NPs	MnO2	CAT, SOD	UC	Oral	ROS, inflammatory cytokines,	[138]
	Ru-MOF	Ru-MOF	CAT, SOD	UC	Oral	ROS, RNS, TNF-related inflammation pathways	[90]
	Ce-Cur@MCS	CeO2	CAT, SOD	UC	Oral	ROS, inflammatory cytokines, macrophage polarization, GPX4 pathway, gut microbiota	[106]
	ZCC NPs	CeO2	CAT, SOD	UC	Oral	ROS, damage-associated molecular patterns (DAMPs), inflammatory cytokines, macrophage polarization, mucus barrier, gut microbiota	[139]
	BL@B-SA50	FeSA	CAT, SOD	UC & CD	Oral	ROS, inflammatory cytokines, intestinal barrier, gut microbiota	[115]
	TMNSs	Ru38Pd34Ni28 nanosheets	CAT, SOD	UC	I.V.	ROS, RNS, inflammatory cytokines,	[140]
	MPDA@CeO2-x NPs	CeO2-x	CAT, SOD	UC	Rectal administration	ROS, inflammatory cytokines, NF-kB signaling pathway, Nrf2 signaling pathway, macrophage polarization, intestinal barrier	[141]
	Au/CeO2@HA	Au/CeO2	CAT, SOD	UC	Oral	ROS, inflammatory cytokines,	[98]
	HA-5-HT@CeO2	CeO2	CAT, SOD	UC	Oral	ROS, MPO inflammation, inflammatory cytokines, intestinal epithelial barrier	[142]
	Bi2Se3 nanodiscs	Bi2Se3	CAT, SOD	UC	I.V.	ROS, RNS, inflammatory cytokines, gut microbiota	[97]
	MnO2@OMVs	MnO2	CAT, SOD	UC	Oral	ROS, inflammatory cytokines, TLR4/NF-кB pathway, intestinal barrier, gut microbiota	[101]
	Pt NPs	Pt	CAT, SOD	UC	Oral	ROS	[143]
	D-CeO2 NPs	CeO2	CAT, SOD	UC&CD	Oral	ROS, inflammatory cytokines, colonic fibrosis	[94]
	CeO2@PDA-PEG	CeO2	CAT, SOD	UC	Oral	ROS, inflammatory cytokines, macrophage polarization	[96]
	Ni3S4 NPs	Ni3S4	CAT, SOD	UC	Oral	ROS, inflammatory cytokines, macrophage polarization, intestinal barrier, gut microbiota	[144]
	PEG-CNPs	Ce NPs	CAT, SOD	UC	Oral	ROS, inflammatory cytokines, macrophage polarization, mucosal barrier	[145]
	Histidine-derived carbon dots	CDs	CAT, SOD	UC	Oral	ROS, inflammatory cytokines, intestinal barrier, gut microbiota	[112]
	TMNR	Melanin	CAT, SOD	UC	Oral	ROS, inflammatory cytokines, intestinal barrier, gut microbiota	[146]
	MnGA NPs	Mn	CAT, SOD	UC	Oral	ROS, RNS, inflammatory cytokines, TLR4/NF-кB pathway, macrophage polarization, intestinal barrier, gut microbiota	[147]
	Cur@PC-HA/CeO2	CeO2	CAT, SOD	UC	Oral	ROS, inflammatory cytokines, TLR4/NF-кB pathway, intestinal barrier, gut microbiota	[148]
	Motor@M2M@SAM	MnO2	CAT, SOD	UC	Oral	ROS, inflammatory cytokines, macrophage polarization, intestinal barrier, gut microbiota	[105]
	SP@CS-SeNPs	Se NPs	CAT, SOD	UC	Oral	ROS, inflammatory cytokines, intestinal barrier	[107]
	PM@Pic/PtCD@NP	PtCD	CAT, SOD	UC	I.V.	ROS, inflammatory cytokines, neutrophils swarming, intestinal barrier	[110]
	Porous manganese-iron PB	MnPB	CAT, SOD	UC	Oral	ROS, inflammatory cytokines	[149]
	SSZ-CuTA NPs	CuTA	CAT, SOD	UC	Oral	ROS, inflammatory cytokines, intestinal barrier	[150]
	Cu2O@His	Cu2O	CAT, SOD	UC	I.V.	ROS, RNS, inflammatory cytokines, mitochondrial damage	[93]
	Cu5.4O@SA	CuS/Cu2S	CAT, SOD	UC	Oral	ROS, RNS, H2S, inflammatory cytokines, intestinal epithelial barrier, gut microbiota	[151]
	BMM/MPs	MnO2	CAT, SOD	UC	Oral	ROS, inflammatory cytokines, macrophage polarization, intestinal epithelial barrier, gut microbiota	[152]
POD, CAT	Glycol chitosan@AuNP	AuNP	POD, CAT	UC	I.V.	ROS, RNS, damage-associated molecular patterns (DAMPs), inflammatory cytokines, macrophage polarization, intestinal barrier, gut microbiota	[153]
	PB@N3	PB	POD, CAT	UC	Oral	ROS, inflammatory cytokines, intestinal barrier, gut microbiota	[154]
POD, SOD	PPy/PFD@Inulin gel	PPy	POD, SOD	UC	Oral	ROS, RNS, inflammatory cytokines, intestinal epithelial barrier, intestinal fibrosis, gut microbiota, TGF-β/Smad signaling pathway	[103]
POD, ORS	Ti3C2-PVP NSs	Ti3C2	POD, ORS	UC	Oral	ROS, inflammatory cytokines, macrophages polarization,	[74]
	W-POM NCs	W-POM	POD, ORS	UC	Oral	ROS,	[84]
Multienzyme activity
	PPB	PB	POD, CAT, SOD	UC	I.V.	ROS	[77]
	2D Co NSs	CoOOH	POD, CAT, SOD	UC	Oral	ROS, inflammasome NLRP3	[87]
	WSe2@F127	WSe2	POD, CAT, SOD	UC&CD	Oral	ROS, RNS, inflammatory cytokines, T cell differentiation, intestinal barrier	[155]
	CCM-Co-ZIF-8	Co-ZIF-8	POD, CAT, SOD	UC	Oral	ROS, inflammatory cytokines, macrophage polarization	[91]
	ZnPBA@YCW	ZnPBA	POD, CAT, SOD	UC	Oral	ROS, inflammatory cytokines, TLR4/NF-кB pathway, intestinal barrier, gut microbiota	[114]
	LiMn2O4	Mn	CAT, SOD, GPx	UC	I.P.	ROS, inflammatory cytokines TNF-α, IL-10	[99]
	halogen-doped CoCN	CoCN	CAT, SOD, GPx	UC	I.V.	ROS	[100]
	MLPPP	Mn3O4	CAT, SOD, GPx	UC	Oral	ROS, inflammatory cytokines, TLR4/NF-кB pathway, intestine barriers	[83]
	Cu,Zn,I-Doped Carbon Dots	Carbon Dots	CAT, SOD, GPx	UC	Oral	ROS, inflammatory cytokines	[156]
	MnNi@PVP	MnNi	CAT, SOD, GPx	UC	Oral	ROS, RNS, inflammatory cytokines, TLR4/NF-кB pathway, macrophage polarization, intestinal barrier	[157]
	Se-CA	Se NPs	CAT, SOD, GPx	UC	Oral	ROS, RNS, inflammatory cytokines, macrophage polarization, iron death, intestinal epithelial barrier, gut microbiota	[158]
	Se0-HMPB	PB, Se	POD, CAT, SOD, GPx	UC&CD	I.V.	ROS, inflammatory cytokines, ferroptosis, T cell differentiation, intestinal barrier	[159]
	PMNFs	Mo3Se4	POD, CAT, SOD, GPx	UC	Oral	ROS, inflammatory cytokines, TLR4/NF-кB pathway	[85]
	Fe/N-HCNs	Fe/Carbon	POD, CAT, SOD, OXD	UC	Oral	ROS, inflammatory cytokine	[160]

In summary, despite these challenges, the opportunities for nanozyme therapy in IBD are still vast. Nanozymes can be readily tailored and adapted, enabling the creation of novel formulations with customized properties and functions. Besides, the modularity of nanozymes enables the integration of multiple functions into a single entity, enabling the creation of multifunctional nanozymes that can address the complex and multifaceted nature of IBD. Furthermore, nanozymes can be easily administered orally, making them a convenient and patient-friendly treatment option. This review thoroughly examined the literature and analyzed the latest research findings to present a comprehensive and up-to-date perspective on the topic. We hope that researchers could gain a deeper understanding of the pathogenic mechanism of IBD and nanozyme therapy via this paper, thereby advancing nanozyme-based therapeutics from single-function agents to multifunctional synergistic systems. We believe the development of nanozyme therapy for IBD is an exciting and rapidly evolving field, with significant potential to transform the treatment of this debilitating disease.

CRediT authorship contribution statement

Fang Lei: Writing – original draft. Qizhen Huang: Writing – original draft. Chengfeng Zhang: Writing – original draft. Youhui Lin: Writing – review & editing. Yan Zhang: Writing – review & editing. Faming Wang: Writing – review & editing, Writing – original draft, Project administration, Funding acquisition.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

No data was used for the research described in the article.