Recent progress in stimuli-responsive hydrogel-based drug delivery for inflammatory bowel disease

1 Introduction

Inflammatory bowel disease (IBD) encompasses a group of chronic, relapsing inflammatory disorders affecting the rectum, colon, and, in some cases, the entire gastrointestinal tract. Its hallmark pathological features include disruption of the intestinal mucosal barrier, dysregulation of immune homeostasis, and gut microbiota dysbiosis (Ouyang et al., 2023), Beyond profoundly impairing patients’ daily functioning and nutritional status, IBD predisposes individuals to severe complications such as intestinal obstruction, perforation, and colorectal cancer, thereby imposing a substantial health-related and economic burden (Zhang et al., 2015). Although recent years have witnessed advances in biologic agents and immunomodulators, suboptimal targeting specificity, insufficient local drug accumulation at the lesion site, and pronounced off-target toxicities remain formidable obstacles that critically constrain therapeutic outcomes (Liu et al., 2025). Consequently, the development of intelligent delivery systems capable of precisely shuttling therapeutics to colonic inflammatory foci has emerged as a pivotal strategy in IBD management (Zhang Q. et al., 2025). Orally administered drugs must negotiate a series of extreme and dynamically changing physiological barriers along the gastrointestinal (GI) tract before reaching the colonic target, and these barriers profoundly influence the efficacy of the delivery process (Xie et al., 2026). First, the highly acidic gastric environment (pH 1.0-2.5), in concert with high concentrations of pepsin, readily induces acid-catalyzed degradation and enzymatic inactivation of probiotics as well as labile bioactive macromolecules such as proteins, peptides, and nucleic acids (Yu et al., 2023). Subsequently, upon entry into the small intestine, the pH rises to near-neutral levels (approximately pH 6.0–7.4), where the robust secretory activity of proteolytic enzyme, including trypsin, chymotrypsin, and carboxypeptidase constitutes a second stringent enzymatic barrier, further compromising carrier integrity and precipitating premature drug leakage (Lu et al., 2025). Even if the delivery system successfully surmounts the aforementioned upper GI barriers, the colonic microenvironment in IBD is far from a homogeneous physiological space. Inflamed tissues are characterized by massive accumulation of reactive oxygen species (ROS), aberrant overexpression of inflammation related enzymes such as matrix metalloproteinases (MMPs), and a modest decrease in local pH (approximately pH 6.Eight in inflamed colonic fluid) features that starkly contrast with the physiological status of healthy colonic tissue (Rial-Hermida et al., 2021). Adding to this complexity is the non-uniform, patchy distribution of IBD lesions interspersed within normal intestinal mucosa, coupled with disruption of the mucus layer and compromised epithelial barrier integrity (Garcia-del Rio et al., 2020). Therefore, an ideal delivery system must not only possess inflammation-specific recognition capabilities but also achieve prolonged retention at the diseased foci and execute on demand drug release in a spatiotemporally controlled manner (Li et al., 2025).

Hydrogels are polymers with a three-dimensional network structure (Ahmed, 2015). Owing to their hydrophilicity, reusability, and excellent biocompatibility (Mehta et al., 2023),they are widely used in the medical field to construct drug delivery systems with sustained-release capabilities, thereby prolonging the duration of drug action (Delgado-Pujol et al., 2025). Hydrogels are sensitive to the gastrointestinal environment, enabling site-specific release and conferring targeting properties that reduce systemic side effects (Ene et al., 2026). Furthermore, they can prolong the residence time of drugs at inflamed sites, enhance anti-inflammatory efficacy, and improve bioavailability and therapeutic outcomes. To further refine delivery precision and lesion specificity, stimuli-responsive hydrogels have been developed (Ding et al., 2026). These hydrogels can sense external stimuli and undergo structural changes; these include swelling, shrinkage, degradation, or sol-gel transitions, enabling on-demand drug release. (Protsak and Morozov, 2025). Based on the origin of the triggering signals, stimuli-responsive hydrogels are primarily categorized into pH-responsive, temperature-responsive, ROS-responsive, and enzyme-responsive types (Sun et al., 2026), Each of these systems offers distinct advantages, enabling recognition and response to the complex inflammatory microenvironment of IBD lesions under diverse physiological conditions, thereby achieving precise delivery (Sun Y. et al., 2025).

Different fabrication methods yield hydrogels with distinct properties. Conventional preparation techniques, such as emulsification and mechanical stirring, typically produce hydrogels with broad particle size distribution and poor batch to batch reproducibility (Li et al., 2021), which preclude precise control over drug encapsulation efficiency and release kinetics and are even less capable of achieving synergistic responsiveness to multiple microenvironmental signals. The introduction of microfluidic technology offers a highly promising solution to these challenges (Liu et al., 2024b). By virtue of the highly controllable laminar shear forces and droplet generation within microchannels, microfluidics enables the fabrication of hydrogels that are highly monodisperse in size, and further allows the construction of complex hierarchical architectures including core shell, multi compartment, and multi component structures, thereby enabling spatially precise arrangement of distinct functional modules, such as acid resistant protective shells, responsive crosslinked networks, and surface targeting ligands) (Shembekar et al., 2016). This endows the hydrogels with programmed responsiveness, allowing them to mount hierarchical responses to gastric acid, proteases, and inflammatory oxidative/enzymatic signals, while maintaining carrier integrity and bioactivity throughout transit across the entire gastrointestinal tract, ultimately executing site specific release and barrier repair functions at IBD lesions.

This review focuses on the classification, preparation methods, and current application status of stimuli responsive hydrogels in IBD therapy (Figure 1). Based on recent studies, we systematically summarize the key mechanisms of action of hydrogels in IBD treatment, including responsive degradation triggered drug release, scavenging of excessive reactive oxygen species, modulation of immune cell functions, promotion of mucosal repair, and regulation of the gut microbiota, which synergistically contribute to therapeutic efficacy. Finally, we discuss future directions for hydrogel development, including multi responsive integrated systems and the construction of integrated platforms combining smart delivery with real time monitoring, with the aim of providing new insights for precision therapy of IBD.

2 Response mechanisms of stimulus-responsive hydrogels and advantages

The intestinal inflammatory microenvironment presents multiple aberrant biochemical signals, including a modest decrease in pH, burst accumulation of ROS, and abnormal overexpression of inflammation associated enzymes such as MMPs and esterases (Yang et al., 2023). These features provide abundant endogenous triggering signals for smart delivery systems. To date, a variety of smart hydrogels responsive to the intestinal inflammatory milieu have been developed to achieve on demand drug release and precision therapy at the lesion sites. Herein, we review the response mechanisms and respective advantages of commonly employed stimuli responsive hydrogels in the context of IBD treatment, as follows.

2.1 pH response

pH-responsive hydrogels represent one of the most extensively studied smart delivery systems to date. Their responsiveness originates from the protonation and deprotonation behavior of ionizable groups such as carboxyl and amino moieties on the polymer chains in response to varying pH conditions (Liu et al., 2024c). For colonic delivery, these hydrogels are commonly fabricated from natural polysaccharides such as alginate (SA), chitosan (CS), hyaluronic acid (HA), and pectin (Qu et al., 2017). Under the strongly acidic gastric environment (pH 1.0-2.5), protonation of carboxyl groups reinforces interchain hydrogen bonding and induces chain contraction, resulting in a dense network that effectively restricts drug diffusion (Shohraty et al., 2016), Upon reaching the small intestine and colon, where the pH rises to near neutral or weakly alkaline conditions (pH 6.8–7.4), deprotonation of carboxyl groups generates a substantial negative charge, and the ensuing electrostatic repulsion drives network swelling and even disintegration, thereby enabling colonic specific drug release (Rodríguez-Rodríguez et al., 2025).

The advantages of pH responsive hydrogels lie in their well-established fabrication processes, broad availability of raw materials, and favorable biocompatibility. However, several limitations persist. The pH signal itself exhibits considerable inter individual variability among IBD patients and shows only a modest decrease (approximately pH 6.8) at inflamed sites (Tie et al., 2021), thus, a single pH responsive mechanism is insufficient to achieve precise discrimination of diseased foci. Moreover, most pH sensitive materials including alginate still suffer from a certain degree of non-specific drug leakage in gastric acid, necessitating further improvements through multilayer coating or composite modification strategies.

2.2 Temperature response

Temperature responsive hydrogels are governed by a reversible sol gel phase transition arising from the temperature dependent shift in the hydrophilic–hydrophobic balance of polymer segments (Lv et al., 2025). Thermosensitive hydrogels applied in IBD therapy primarily capitalize on the temperature differential between body temperature (approximately 37 °C) and ambient conditions (25 °C): they exist as freely flowing sols at room temperature for convenient administration via injection or enema, and undergo rapid gelation upon entry into the body, forming a semi solid physical barrier over the colonic mucosal surface (Das et al., 2024). According to their phase transition behavior, these hydrogels can be categorized into LCST (lower critical solution temperature, exhibiting shrinkage upon heating) and UCST (upper critical solution temperature, exhibiting swelling upon heating); among these, the LCST characterized by a sol to gel transition upon warming from ambient to body temperature represents the most adopted configuration in IBD delivery systems (Gou et al., 2026).

The advantages of temperature responsive hydrogels lie in their straightforward administration, mild gelation conditions that eliminate the need for external crosslinking agents or photo initiators, and the capacity of the resulting three-dimensional network to serve directly as a physical barrier against pathogen invasion (Joubert et al., 2019). However, the gelation behavior of these systems depends heavily on physical crosslinking among hydrophobic polymer segments, rendering the network density and mechanical strength at body temperature susceptible to inter individual thermal fluctuations. Moreover, these hydrogels are prone to non-specific erosion under the continuous shear forces generated by intestinal peristalsis (Tang et al., 2021), which compromises longtermly barrier stability and sustained drug release at the lesion sites. Furthermore, a single temperature responsive mechanism lacks active recognition of the inflammatory microenvironment, precluding lesion specific drug release. Consequently, integrating temperature responsiveness with pH, ROS, or enzyme responsive modules is essential to construct multi-level synergistic delivery systems.

2.3 ROS response

The respiratory burst of neutrophils and macrophages at IBD inflammatory sites generates abundant ROS, elevating lesional ROS levels to 10–100 times those in normal tissues (Xing et al., 2026). This pronounced concentration gradient differential provides a highly specific triggering signal for ROS-responsive delivery systems. In response to this specific trigger, the ROS concentration gradient, the gradient, the design strategies for ROS-responsive hydrogels can be categorized into two major classes based on their chemical mechanisms. One class relies on the incorporation of ROS-cleavable chemical bonds including diselenide, thioketal, and arylboronic ester moieties), which undergo cleavage in ROS-overexpressing environments, thereby inducing degradation or structural reorganization of the polymer network (Wang et al., 2017). The other class exploits the oxidizing nature of ROS to convert thiol groups into disulfide bonds, thereby forming a crosslinked network in situ at inflammatory sites and achieving gelation (Zhang et al., 2017). Both strategies leverage the markedly elevated ROS levels at the lesional sites to endow the delivery systems with high spatial selectivity in responsiveness.

The advantages of ROS-responsive hydrogels lie in the high inflammatory specificity of the responsive signal (the ROS concentration gradient), which enables precise recognition of the lesional microenvironment and on demand drug release (Xiong et al., 2026), In addition, the incorporation of chemical bonds such as diselenide and phenylboronic ester moieties confers supplementary antioxidant properties to the materials, synergistically scavenging excessive ROS (Wang et al., 2025; Robert Stern, 2006). Nevertheless, several limitations warrant attention: the synthetic routes for ROS-responsive chemical bonds are generally intricate and costly; the pronounced spatiotemporal heterogeneity of ROS levels in vivo may result in non-uniform responsiveness (Saravanakumar et al., 2016), and the long-term biosafety of certain selenium or boron containing materials requires systematic evaluation.

2.4 Enzyme response

The activity of multiple enzymes is markedly aberrant in the IBD inflammatory microenvironment, including overexpression MMP, upregulation of esterase activity, and excessive activation of hyaluronidases (Moreira Teixeira et al., 2012), These abnormalities provide highly specific triggering mechanisms for enzyme-responsive delivery systems. The design of enzyme-responsive hydrogels typically involves the incorporation of enzyme-specific cleavage sequences including, MMP-degradable peptide segments or ester bond-containing structural moieties into the crosslinked network. Upon enzymatic cleavage at the inflammatory sites, these hydrogels undergo network degradation, swelling, or structural transformation, thereby achieving on-demand drug release (Qi et al., 2025).

The advantages of enzyme-responsive hydrogels reside in their exceptionally high specificity: inflammation-associated enzymes are expressed at substantially higher levels at the lesional sites than in normal tissues, enabling precise pathological microenvironment recognition. Moreover, enzymatic catalysis proceeds under mild conditions with high efficiency, facilitating rapid on-demand drug release (Thornton et al., 2007). Nevertheless, several limitations are equally evident. The expression profiles and activities of these enzymes vary considerably across individual patients and at different stages of disease progression, posing challenges for universal dose regulation. The accessibility of enzymes is also influenced by the network density of the hydrogel and the mucus layer overlaying the lesions. Additionally, the introduction of enzyme-responsive modules such as peptide sequences may elevate the immunogenicity risk of the materials.

In summary, each of the four stimuli-responsive mechanisms described above operates via a distinct trigger signal (Table 1). pH-responsive hydrogels exploit the gastrointestinal pH gradient to achieve colon-targeted drug release; they benefit from well-established fabrication processes but suffer from insufficient specificity. Temperature-responsive hydrogels leverage body temperature to trigger in situ gelation, offering convenient administration yet lacking active inflammatory targeting. ROS-responsive hydrogels utilize the elevated ROS levels at inflammatory foci as the trigger, affording high specificity along with additional ROS-scavenging capacity; however, they are hampered by complex synthesis and pronounced in vivo heterogeneity. Enzyme--responsive hydrogels capitalize on the overexpression of inflammation associated enzymes for lesion specific drug release, with high catalytic efficiency, but are challenged by inter-patient variability in enzyme profiles and difficulties in universal design. Given that a single responsive mechanism is inadequate to address the complexity and dynamics of the IBD inflammatory microenvironment, the integration of multiple responsiveness has emerged as a central trend in current research.

TABLE 1. Comparison of different stimuli-responsive mechanisms, advantages, and limitations of hydrogels for IBD therapy.

2.5 Multi-stimulus response

By integrating multiple responsive mechanisms into a single carrier, hydrogel systems can trigger sequential drug release in distinct gastrointestinal segments according to the spatiotemporal features of IBD pathology: gastric acidity activates protective contraction to resist enzymatic degradation, the near-neutral pH of the colon induces framework swelling for lesion localization, and finally, elevated ROS or enzyme signals at inflammatory sites drive on-demand drug release, thereby establishing a programmed delivery platform. Geng and colleagues developed pH/enzyme dual-responsive gel microspheres (MSZ/HP-β-CD/DA-SA/KGM/CS) that exploit the pH sensitivity of alginate and the colon-specific enzymatic degradability of konjac glucomannan (KGM) (Geng et al., 2025), achieving stability in gastric acid and a drug release rate of up to 85.3% upon β-mannanase triggering in the colon, while attenuating DSS-induced colonic inflammation in UC rats through downregulation of the TLR4/MyD88/NF-κB pathway. Inspired by disulfide bond-mediated mucin adhesion. Hao and co-workers constructed a pH/redox dual-responsive thiolated alginate hydrogel (Hao et al., 2023), which utilizes carboxyl protonation/deprotonation for gastric protection and small intestinal release, while disulfide bond cleavage in the colonic reducing environment drives complete degradation; concomitantly, free thiol groups enhance mucosal adhesion, achieving a 10⁵-fold increase in probiotic survival. The advantage of multi-responsive integrated hydrogels lies in their capacity to translate the anatomical gradients of the gastrointestinal tract and the pathological signals of IBD into temporally orchestrated delivery instructions. Such systems not only enhance the spatiotemporal precision of drug delivery but also improve lesion specificity through synergistic multi-signal recognition, thereby minimizing off-target drug exposure. Future investigations should further explore the logical matching and sequential optimization of distinct responsive signal combinations to advance the development of more intelligent and controllable programmed delivery systems.

3 Methods for the synthesis of stimulus-responsive hydrogels

Based on the multi-responsive nature of the IBD lesion microenvironment encompassing pH gradients, temperature, ROS, and specific enzymes various smart hydrogel-based delivery systems have been developed to achieve intestinal targeting and on-demand drug release (Wen et al., 2023). The realization of the responsiveness relies critically on the rational design of the hydrogel carrier microstructure and its precise fabrication. At present, emulsification, droplet microfluidics, and electrospraying constitute the three mainstream techniques for preparing hydrogel microspheres. These three fabrication methods each offer distinct trade-offs across three core dimensions: particle size, bioactive retention, and scalability (Wu et al., 2025).

3.1 Emulsification method

Permission must be obtained for use of copyrighted material from other sources (including the web). Please note that it is compulsory to follow figure instructions. Emulsification is the most classical and widely employed technique for microsphere preparation. Its fundamental principle involves dispersing an aqueous phase containing polymers and bioactive cargoes into an immiscible oil phase, forming a water-in-oil (W/O) emulsion through mechanical stirring or homogenization (Cho, 2005),followed by droplet solidification via chemical crosslinking, ionic crosslinking, or solvent evaporation to yield microspheres (Ding et al., 2019). This method offers outstanding advantages in large-scale production, including operational simplicity, low equipment requirements, and cost-effectiveness, rendering it the most industrially mature processing route to date (Figure 2).

Despite these practical benefits, conventional emulsification still exhibits notable limitations in precision delivery scenarios. The shear forces generated by mechanical stirring are inherently non-uniform, resulting in a broad size distribution of the resulting microspheres and precluding precise control (Li et al., 2021). Moreover, the oil phase necessitates the use of organic solvents such as mineral oil, cyclohexane and surfactants such as Span 80 (Lovell and Schork, 2020), incomplete removal or residual traces may elicit cytotoxicity or inflammatory responses. In simulated gastric fluid, the viability of encapsulated probiotics remains only approximately 7%–22%, indicating relatively limited protective capacity (Zheng et al., 2017). In terms of drug loading and release, conventional emulsification commonly suffers from low encapsulation efficiency, with significant drug leakage during solvent evaporation, leading to pronounced burst release and delayed release phenomena that are difficult to finely regulate (Yan et al., 2017). Furthermore, this method faces severe challenges in cutting-edge applications requiring high safety and uniformity, such as advanced drug delivery and cell therapy (Silva et al., 2016). Thus, although conventional emulsification retains an important position in industrial-scale production, its inherent limitations are driving researchers to explore novel fabrication technologies such as microfluidics and membrane emulsification to achieve more precise and gentler microsphere manufacturing (Cai et al., 2014).

3.2 Electrospray method

Electrospray technology utilizes a high-voltage electric field to generate charged droplets from the tip of a Taylor cone. By modulating parameters such as voltage, flow rate, and collection distance (Gañán-Calvo et al., 2018), it can produce microspheres with good size uniformity (coefficient of variation <10%) and excellent bioactive retention (Feng et al., 2023). Its mild electric field and room-temperature operating conditions render it promising for pilot-scale production and the development of high-value products. Depending on the droplet collection mode, electrospray is classified into dry electrospray and wet electrospray (Huang et al., 2022; Mezquita et al., 2017).

Dry electrospray employs a solid plate as the collector, yielding solid particles rather than fibers (Jia et al., 2025). The process proceeds as follows: a polymer solution is ejected through a nozzle under high voltage, forming a Taylor cone; during flight, the solvent evaporates, and upon impacting the collection plate, the droplets solidify (Figure 3A). The properties of the resultant particles are governed by electrospray parameters (voltage, flow rate, collection distance), polymer characteristics, and the type and concentration of crosslinking agents.

Wet electrospray utilizes a liquid bath as the collection device, enabling direct harvesting of microgels, and is generally superior to dry electrospray (Tapia-Hernández et al., 2015). This method is further divided into the Singel stage procedure and the Double stage procedure (Figures 3C,D): in the Singel stage procedure, the polymer solution is sprayed directly into a receiving liquid containing the crosslinker to form mixed-matrix microgels; in the Double stage procedure, the crosslinker solution is first sprayed to generate a gel core, which is then immersed in a shell solution for coating, yielding a more compact core–shell structure (Zhang et al., 2022) (Figure 3B). The properties of the microgels are influenced collectively by polymer properties, crosslinking conditions, and electrospray parameters. However, technical challenges such as electric field interference during the electrospray process constrain its application in large-scale industrial production.

3.3 Microfluidics method

Microfluidic technology, by virtue of its microchannels and fluidic control systems, enables precise manipulation of micro scale droplets, particles, or cells (Liu et al., 2024b; Sun Z. et al., 2025). Droplet microfluidics can generate highly monodisperse, size controllable droplets under stable and enclosed contamination free conditions, making it an ideal platform for constructing hydrogels. This method allows precise regulation of flow rates, mixing ratios, and reaction conditions within microchannels, thereby ensuring the accurate synthesis of microgel materials. Furthermore, its high throughput capability supports batch production of microgels with tunable size, morphology, and composition, significantly enhancing process controllability and reproducibility (Zhang et al., 2025a).

A typical workflow for hydrogel fabrication via microfluidics includes droplet generation, crosslinking induced gelation, and subsequent collection and washing (Figure 4). The fundamental mechanism of droplet formation arises from the interplay between interfacial tension and shear forces when the dispersed phase meets an immiscible continuous phase, leading to dynamic breakup of the liquid column and eventual minimization of interfacial energy. Based on channel geometry, the commonly employed designs are T junction, flow focusing, and co flow configurations (A. S. Utada, 2007) (Figure 4A). In the T junction geometry, two immiscible fluids converge at the junction; the dispersed phase is pinched off under the pressure and shear exerted by the continuous phase, generating droplets (Hinojosa-Ventura et al., 2023). He flows focusing configuration brings three fluid streams together at a cross shaped intersection; the dispersed phase is symmetrically squeezed by the continuous phase from both sides, leading to droplet breakup. The co flow configuration employs a tapered capillary inserted along the channel axis (Hu et al., 2015), the dispersed and continuous phases flow in parallel into the main channel, where the shear from the continuous phase promotes droplet formation. Droplets generated via these methods typically form spherical water in oil (W/O) emulsions, with the oil phase as the continuous phase and the aqueous phase as the dispersed phase (Lück et al., 2016). Commonly used oil phases include hydrocarbon oils including paraffin oil, n hexene (Allazetta et al., 2013) and fluorocarbon oils including hydrofluoroether (Utech et al., 2015), perfluoro tripropylamine (Sheikhi et al., 2019). Fluorocarbon oils are favored in biomedical applications due to their low viscosity, high oxygen permeability, and favorable biocompatibility (Shen et al., 2016). To stabilize droplets and prevent coalescence, surfactants are usually added to the oil phase (Ya-Ling Chiu et al., 2014). The aqueous dispersed phase generally contains a hydrogel precursor solution including crosslink able polymers or monomer along with initiators and crosslinkers. Cells or drugs can also be incorporated into this phase to achieve encapsulation of bioactive substances during gelation (Lin et al., 2022). In addition, multi-channel aqueous streams can combine different solutions to tailor the composition and functionality of the final microgels (Chai et al., 2021; Mehraji et al., 2024), The resulting droplets are highly monodisperse and reproducible, and their size can be controlled by adjusting the viscosity of the aqueous phase, the flow rates of the two phases, and the characteristic dimensions of the microchannels (Jiang et al., 2014) (Figure 4B). After droplet generation and crosslinking solidification, the water in oil emulsion must be subjected to demulsification to separate and purify the resulting microgels. A typical demulsification procedure is as follows: first, the emulsion containing the solidified microgels is collected and allowed to stand to ensure sufficient crosslinking; then, a emulsifier is added to disrupt the oil water interfacial film, thereby separating the oil phase from the aqueous phase. After shaking or centrifugation, the upper oil phase and the demulsified are removed, and the microgels at the bottom are collected. Finally, the microspheres are washed several times with PBS buffer to remove residual oil phase and surfactants from their surface (Figure 4C). Droplet microfluidics, leveraging precise shear force control within microchannels, can produce near ideal monodisperse microspheres with a coefficient of variation below 3%, making it the optimal approach among the three fabrication techniques in terms of size uniformity. Under ambient temperature, organic solvent free, and mild crosslinking conditions, this technology maximizes the retention of bioactivity approximately 70% of encapsulated functional proteins remain active and the controlled release profile can be precisely modulated by adjusting the microsphere diameter (Jin et al., 2024; Aikawa et al., 2011).

3.4 Design trade-offs for hydrogels used in the treatment of IBD

The three fabrication methods described above each possess distinct advantages and limitations in terms of particle size uniformity, bioactive retention, and scalability. However, the selection of an optimal process–material combination requires systematic trade-offs among multiple interdependent design parameters. Hydrogel stiffness determines its resistance to deformation under intestinal peristalsis (excessively soft hydrogels are prone to erosion, whereas excessively stiff ones may damage the mucosa). Mesh size and swelling ratio jointly influence drug diffusion and the encapsulation efficiency of macromolecular cargos such as antibodies and probiotics. Degradation kinetics must align with the fluctuating inflammatory cycles of IBD—rapid drug release is required during acute flares to control fulminant inflammation, whereas sustained release is needed during remission to maintain barrier integrity. Mucoadhesiveness correlates with intestinal retention time, yet excessive adhesion may cause non-specific retention at healthy sites. Ligand density affects lesion-targeting efficiency, but over-densification may increase immunogenicity risks. Drug loading capacity and release kinetics are mutually constrained—high loading often leads to burst release, necessitating core–shell or multicompartment architectures to achieve a balanced profile.

Gangurde reviewed pH-responsive hydrogels for oral colon-targeted biologic delivery (Gautami et al., 2026), covering the thermodynamic and kinetic mechanisms of pH-triggered swelling, including Flory–Rehner theory, Donnan osmotic swelling, mesh size dynamics, and Korsmeyer–Peppas release modeling. The authors compared natural polysaccharides (alginate, chitosan, pectin, hyaluronic acid) and synthetic polymers (Eudragit® S100, polyacrylic acid, itaconic acid–acrylamide nanogels) for delivering monoclonal antibodies, siRNA, and exosomes, and summarized how crosslinking strategies, ionotropic, polyelectrolyte, dynamic covalent, and layer-by-layer affect gel stability, biosafety, and release behavior. The review also addressed pH/ROS and enzyme-responsive systems for IBD-targeted therapy, alongside translational challenges in manufacturing, bioactivity preservation, and regulation. Overall, this work offers a systematic reference for material design and clinical translation in the field. Chen et al. constructed a series of stiffness-tunable CMOT hydrogels via dynamic Schiff-base crosslinking, achieving precise modulation of mechanical properties (Chen et al., 2026). They found that the moderately stiff CMOT-M hydrogel (212.5–416.5 Pa) most closely mimics native colonic tissue (235.1–642.5 Pa) and exhibited the best mucosal healing efficacy in DSS-induced colitis mice. Mechanistically, the CMOT-M hydrogel modulates the Hippo signaling pathway through integrin-cytoskeletal tension transduction, moderately activating YAP/TAZ during the acute phase to promote epithelial proliferation and migration, while suppressing over-activation during the repair phase to guide stem cell differentiation and prevent fibrosis. This finding demonstrates that material stiffness can serve as a physical design parameter, independent of biochemical signals, to directly regulate tissue repair processes through mechanotransduction pathways.

Ultimately, the rational design of hydrogels represents a multi-objective optimization problem that seeks the optimal balance among pathological microenvironment requirements, material chemistry constraints, and fabrication feasibility.

4 The application of stimulus-responsive hydrogels in the treatment of IBD

4.1 Maintained the intestinal barrier

The intestinal mucosal barrier, primarily composed of the mucus layer and tight junctions between epithelial cells, is essential for nutrient absorption and pathogen exclusion (Fu et al., 2024). Disruption of this barrier is a key pathological feature of IBD. Hydrogels can contribute to the maintenance and repair of intestinal barrier function through two primary mechanisms: serving as a physical barrier substitute to cover the lesions, and delivering bioactive molecules to promote endogenous repair, thereby playing a critical role in IBD therapy.

Guo et al. administered a PDLLA-PEG-PDLLA thermosensitive hydrogel via enema to DSS-induced colitis mice (Fu et al., 2024; Guo et al., 2024). Upon reaching body temperature, the hydrogel underwent in situ gelation, forming a physical shielding layer over the colonic surface. In vitro Transwell assays demonstrated that this gel effectively impeded the trans-membrane migration of Staphylococcus aureus and Escherichia coli. Remarkably, even without any drug loading, the physical barrier effect alone significantly alleviated colitis symptoms. Similarly, inspired by the biological functions of native mucus, Li et al. developed a PHE-EK biomimetic mucus hydrogel (Cao et al., 2024; Guangshuai Zhang et al., 2024). This hydrogel exists as a free-flowing liquid at room temperature but gelled within 10 s upon exposure to body temperature, exhibiting a fracture strain of 77.8%, favorable mechanical strength, and good resistance to dilution. It functions as an artificial mucus layer covering the damaged colonic surface, shielding against pathogen and antigen invasion, and specifically adheres to inflamed sites through electrostatic interactions (negatively charged hydrogel binding to positively charged proteins exposed at the inflamed mucosa). Wang et al. developed ATG-CS-Gel, a representative ROS-responsive hydrogel that repairs the barrier through molecular modulation (Cao et al., 2024). This hydrogel incorporates diselenide bonds as ROS-sensitive linkers, enabling triggered drug release under excessive ROS at inflammatory sites. In the DSS-induced colitis mouse model, ATG-CS-Gel significantly inhibited MLCK activation, thereby preventing the endocytic degradation of tight junction proteins ZO-1 and Occludin, restoring their expression to near-normal levels. FITC-dextran permeability assays confirmed that this ROS-responsive hydrogel effectively reduced intestinal permeability. Keane et al. proposed a strategy that relies not on drug delivery but solely on the intrinsic bioactivity of extracellular matrix (ECM) materials to repair the barrier (Keane et al., 2016). They prepared an ECM hydrogel (ECMH) from porcine small intestinal submucosa, which, upon enema administration, gelled in situ at the inflamed colonic sites and adhered for over 24 h. In a DSS-induced rat colitis model, ECMH treatment significantly reduced intestinal permeability (as assessed by TRITC-dextran permeability assay) and upregulated epithelial E-cadherin expression. Ex vivo experiments showed that ECMH treatment significantly restored TEER values in LPS-damaged Caco-2 monolayers, accompanied by an approximately 50% increase in E-cadherin-positive cells. Mechanistically, ECMH remodeled the local inflammatory microenvironment by reducing the number of CD68⁺TNFα⁺ M1 pro-inflammatory macrophages (without altering total macrophage numbers), indirectly creating favorable conditions for endogenous epithelial repair. The key finding of this study was that ECM hydrogel indirectly promoted colonic epithelial barrier integrity and functional restoration by steering the local immune microenvironment toward a reparative phenotype.

Kumar et al. utilized self-assembly of glyceryl monostearate (GMS) to prepare an esterase-responsive hydrogel (ER-hydrogel) encapsulating budesonide for rectal administration (Kotla and Rochev, 2023). Owing to its negative zeta potential (−38.4 mV), the hydrogel selectively adhered to the positively charged inflamed mucosa via electrostatic interactions and released the drug on demand upon esterase triggering. This treatment significantly restored goblet cell numbers and mucus layer thickness and HID-AB staining confirmed the restoration of the normal ratio of sulfated to sialylated mucins Fu et al. constructed a supramolecular assembly based on host–guest chemistry (Fu et al., 2024; Zhang et al., 2024), anchoring IGF-1C peptide to a HA backbone via adamantane-β-cyclodextrin interactions (HA-β-CD-IGF-1C). This hydrogel specifically targeted intestinal stem cells through HA-CD44 receptor binding and sustained the release of IGF-1C, significantly upregulating the expression of ZO-1, Occludin, and E-cadherin. Immunofluorescence revealed continuous and uniform distribution of tight junction proteins along the intestinal villi, and both FD4 permeability assays and IVIS live imaging confirmed effective restoration of intestinal barrier integrity.

Based on these studies, it is evident that stimuli-responsive hydrogels maintain intestinal barrier function primarily through two mechanisms: physical covering and molecular modulation (Guangshuai Zhang et al., 2024). However, physical barrier hydrogels suffer from insufficient long-term stability under intestinal peristalsis, and the spatiotemporal matching between drug release kinetics and barrier repair processes in molecularly modulating hydrogels remains imprecise; moreover, the synergistic effects of both mechanisms have not been fully exploited (Xiong et al., 2025). Future efforts should be directed toward developing multifunctional hydrogels that combine high mechanical strength with responsive degradation properties and leveraging microfluidic technology to construct core-shell microgels that enable chronological synergy between physical shielding and on-demand drug release, ultimately achieving concurrent restoration of both the anatomical structure and physiological function of the intestinal barrier.

4.2 Clear intracellular ROS

Macrophages play a central regulatory role in the immunopathological progression of IBD. Under physiological conditions, intestinal lamina propria macrophages are predominantly M2 polarized, maintaining immune tolerance through the secretion of anti-inflammatory cytokines such as IL 10. In IBD lesions, however, large numbers of infiltrating monocytes differentiate into M1 type macrophages under pro inflammatory signals, continuously releasing TNF α, IL 6, and IL 1β (Hassan et al., 2024). M1 macrophages generate abundant ROS, which in turn activate the NF κB pathway, further promoting monocyte differentiation toward the M1 phenotype, thereby establishing a positive feedback vicious cycle of “ROS→M1 polarization→more ROS” (Kim and Kim, 2021). Disrupting this cycle hinges on the elimination of excessive ROS at the lesion sites, which not only directly alleviates oxidative stress damage but also removes the persistent stimulus driving M1 polarization, thus creating a favorable microenvironment for M2 type macrophage polarization. Consequently, regulating macrophage polarization from the M1 to M2 phenotype has become a key strategy in IBD immunotherapy, and ROS responsive hydrogel delivery systems have emerged as powerful tools to achieve this goal by precisely scavenging excessive ROS at inflamed sites (Seo, 2014).

Zhang et al. designed an orally administrable thiolate hyaluronic acid (HA-SH) hydrogel precursor solution based on an ROS triggered in situ gelation mechanism (Zhang et al., 2017). This system exploits the excessive ROS at inflammatory sites to oxidize thiol groups of HA-SH into disulfide bonds, enabling lesion specific gelation and forming an artificial mucus layer that physically shields intestinal epithelial cells from bacterial stimulation. In DSS induced acute and chronic colitis models, HA-SH hydrogel significantly reduced the proportion of F4/80⁺CD86⁺ M1 macrophages in colonic tissues, while increasing the infiltration of F4/80⁺CD206⁺ M2 macrophages and Foxp3⁺CD4⁺ regulatory T cells. Mechanistically, this hydrogel blocks direct contact between bacteria and the epithelium through a physical barrier, inhibiting the persistent activation of the TLR/NF κB pathway by pathogen associated molecular patterns, thereby reducing M1 polarizing signals and promoting the establishment of an M2 dominant immune microenvironment.

Zhou et al. constructed a MnCe@LR/AMs alginate microsphere delivery system through a nanozyme probiotic hydrogel synergistic strategy (Zhou et al., 2025). This system incorporates Mn@CeO₂ nanozymes anchored on the surface of Lactobacillus reuteri, encapsulated within alginate hydrogel microspheres prepared by electrospray. In vitro experiments demonstrated that upon uptake by LPS activated RAW264.Seven macrophages, MnCe@LR/AMs scavenged intracellular ROS via the Superoxide Dismutase/Catalase (SOD/CAT) enzymatic activity of the nanozymes, significantly downregulating the positivity rate of the M1 marker CD86 while upregulating that of the M2 marker CD206. ELISA results further confirmed that the supernatant from this treatment group exhibited markedly reduced levels of TNF α and IL 1β, alongside elevated levels of IL 4 and IL 10. In the DSS induced colitis mouse model, flow cytometry analysis revealed that MnCe@LR/AMs effectively reduced the M1/M2 ratio in the colonic lamina propria and achieved active targeting of macrophages at inflammatory sites through specific binding of alginate to the mannose receptor, synergistically reversing the inflammatory microenvironment at both the ROS scavenging and immunomodulatory levels.

ROS responsive hydrogels can regulate macrophage polarization through two hierarchical mechanisms: extracellular microenvironmental intervention and intracellular direct scavenging. At the extracellular level, hydrogels act as physical barriers to block pathogen-epithelial contact, cutting off upstream stimuli that drive ROS production and indirectly creating conditions conducive to M2 polarization. This approach offers a broad intervention range without reliance on cellular uptake but is constrained by the mechanical stability and sustained durability of the barrier (Guangshuai Zhang et al., 2024). At the intracellular level, following macrophage internalization, hydrogels directly scavenge intracellular ROS, fundamentally interrupting the “ROS→NF-κB→M1 polarization” intracellular signaling axis. This approach features precise targeting and direct action on the polarization signaling pathway yet depends on macrophage endocytosis efficiency and the duration of intracellular activity.

Nevertheless, current research still faces three major challenges. In terms of synergistic strategies, the integration of extracellular upstream blockade with intracellular downstream elimination has not yet established a clear design paradigm. Regarding dynamic adaptation, macrophage polarization states evolve dynamically with disease stage, whereas most hydrogel drug release kinetics are fixed, making spatiotemporal matching with the polarization process difficult (Kim and Kim, 2021). With respect to multi target synergy, there are close interactions among immune regulation, barrier repair, and microbiota modulation, yet current studies are mostly confined to a single target. Future directions should focus on hydrogels that enable cascaded regulation from shutting off stimulation sources to clearing intracellular signals and integrate multi target synergistic delivery, aiming for a more comprehensive reconstruction of intestinal immune homeostasis in IBD (Hassan et al., 2024).

4.3 Regulate gut microbiota

Hydrogel-based delivery systems exhibit potent immunomodulatory potential in IBD therapy, with the core mechanism residing in their ability to break the vicious inflammatory cycle through concurrent restoration of gut microbial homeostasis and elimination of oxidative stress signals. The bidirectional driver relationship between gut dysbiosis and immune dysregulation constitutes the fundamental pathological basis for the persistence of IBD inflammation (Nagayama et al., 2025). Dysbiosis leads to sustained activation of lamina propria immune cells by pathogen-associated molecular patterns such as LPS), inducing M1 macrophage polarization and pro-inflammatory cytokine release; conversely, the inflammatory microenvironment particularly ROS bursts, further suppresses beneficial bacterial growth while promoting opportunistic pathogen proliferation, forming a self-reinforcing loop in which dysbiosis triggers immune activation, immune activation drives inflammation, and the inflamed milieu in turn suppresses commensals while facilitating pathogen expansion (Sharma et al., 2025). Hydrogel delivery systems address this bidirectional feedback loop through synchronous intervention by integrating probiotic delivery and ROS-scavenging functions within a single carrier.

Zhou et al. constructed a layer-by-layer self-assembled chitosan/sodium alginate-coated genetically engineered probiotic E. coli (Nissle) 1917 (ECN-pE(C/A) ₂) (Zhou et al., 2022). This delivery system protects orally administered probiotics from gastric acid degradation through a biocompatible coating, releasing engineered bacteria that CAT and SOD at colonic inflammatory sites. In a DSS-induced colitis mouse model, ECN-pE(C/A) ₂ significantly reduced colonic tissue levels of pro-inflammatory cytokines IL-1β, TNF-α, and IL-6, while elevating anti-inflammatory factors IL-10 and TGF-β. Immunofluorescence revealed restoration of tight junction proteins ZO-1 and Occludin to normal levels. Notably, the engineered probiotics also significantly increased the relative abundance of butyrate-producing bacteria Lachnospiraceae_NK4A136 and Odoribacter, while suppressing proliferation of the pathogenic genus Escherichia Shigella. When gut commensals were depleted by antibiotics, therapeutic efficacy was markedly attenuated, suggesting that gut microbiota remodeling constitutes a key mechanism underlying the immunomodulatory action of ECN-pE(C/A) ₂.

Guo et al. through machine learning and bioinformatics analysis, identified that the abundance of the genus Lactobacillus was significantly reduced in the gut of UC patients (Guo et al., 2024), correlating negatively with elevated oxidative stress levels. Based on this finding, the researchers developed Se-fLac, a selenium dot (Se dot) -functionalized Lactobacillus formulation, which belongs to the category of live biotherapeutic products. The core innovation of this strategy lies in anchoring selenium nanoparticles possessing potent ROS-scavenging activity onto the periplasmic membrane of Lactobacillus via in situ confined crystallization, thereby integrating antioxidant defense and microbiome modulation functions within a single vehicle. Upon oral administration, the composite armor composed of the periplasmic membrane and selenium dots enhances gastric acid tolerance and intestinal mucosal adhesion of the strain. Upon reaching colonic lesions, the selenium dots efficiently scavenge free radicals including O₂ ⁻, ·OH, and NO (ESR signal approaching baseline), while Lactobacillus elevates SCFA levels, particularly butyrate, through modulation of the gut microbiota. In the DSS-induced colitis mouse model, Se-fLac significantly reduced the proportions of Th17 cells and M1 macrophages while increasing the proportion of Treg cells (1.8-fold higher than the PBS group). GPR43 knockout experiments confirmed that SCFAs mediate Treg cell expansion through the GPR43 receptor. In a non-human primate UC model, Se-fLac effectively reduced fecal 8-OHdG levels (a marker of ROS-induced damage) and serum inflammatory markers (CRP), with both colonoscopy and histological analysis demonstrating marked alleviation of intestinal mucosal inflammation.

Collectively, these studies demonstrate that hydrogel/biofilm-coated probiotic delivery systems can achieve systematic remodeling of the IBD inflammatory microenvironment through multiple immunomodulatory pathways, including ROS scavenging, modulation of microbial community structure, and promotion of SCFA-mediated Treg cell differentiation. However, several critical challenges remain. The genetic stability and metabolic activity of engineered probiotics over prolonged in vivo maintenance remain uncertain, making precise clinical control difficult. The spatiotemporal matching between selenium dot release kinetics and strain activity in Se-fLac also requires further optimization. The precision of microbiota regulation is insufficient; current strategies predominantly rely on single-strain supplementation and broad-spectrum SCFA elevation and are not yet capable of achieving precise restoration of specific depleted genera. Moreover, the dysbiotic profiles of UC patients exhibit substantial inter-individual variability, and no clear strategy has been established for personalized microbiota remodeling. With the deepening integration of synthetic biology and materials engineering, hydrogel-probiotic synergistic delivery systems are poised to emerge as a promising direction for multi-target precision therapy in IBD.

4.4 Regulate the immune system

At IBD lesions, compromised intestinal barrier integrity and pathogen invasion drive massive macrophage polarization toward the M1 phenotype, which continuously releases pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β, thereby exacerbating inflammatory responses and tissue injury (Dionne et al., 2017). Conversely, M2-polarized macrophages secrete anti-inflammatory factors such as IL-10 and TGF-β, promoting tissue repair and inflammation resolution. Hence, inducing the transition from M1 to M2 has become a key strategy in IBD immunotherapy. Hydrogels can regulate the intestinal immune microenvironment by modulating macrophage polarization status and the pro-inflammatory/anti-inflammatory cytokine balance, thus playing a pivotal immunomodulatory role in IBD therapy.

Liu et al. designed orally administered, colon-targeting adhesive core–shell hydrogel microspheres (HAMs) (Liu et al., 2021), with a core composed of HA-SH crosslinked with Ag⁺ and a calcium alginate shell. In vitro studies demonstrated that HA-SH significantly suppressed LPS-induced mRNA expression of IL-6, IL-1β, and TNF-α in iBMDM cells by downregulating the NF-κB and MAPK signaling pathways, as evidenced by markedly reduced protein levels of P-IκBα, P-IKKα/β, P-P38, and P-JNK. Meanwhile, HA-SH substantially upregulated the expression of M2-associated genes (IL-10, Arg-1, and Fizz-1), indicating an anti-inflammatory effect mediated by induction of M2 macrophage differentiation. In a DSS-induced colitis mouse model, HAMs significantly reduced the expression of the M1 marker iNOS in colonic tissues while upregulating the M2 marker Arg-1; immunofluorescence staining further confirmed that HAMs promoted the accumulation of CD68⁺CD163⁺ M2 macrophages and suppressed CD68⁺iNOS⁺ M1 macrophages. Moreover, HAMs markedly decreased serum levels of TNF-α, IL-6, and IL-1β while increasing the repair-associated factor TGF-β, effectively ameliorating colitis symptoms.

Lei et al. encapsulated curcumin (CUR) and emodin (EMO) nano formulations (CUR/EMO NE@SA) within a pH-responsive hydrogel to achieve colon-targeted immunomodulation (Lei et al., 2023). This hydrogel significantly inhibited LPS-induced TNF-α and IL-6 expression in activated RAW264.Seven macrophages while promoting IL-10 release in vitro. CUR and EMO synergistically suppressed the NF-κB pathway, reducing phosphorylated p65 and IκBα levels and blocking pro-inflammatory signaling at the upstream level. In DSS-induced colitis mice, CUR/EMO NE@SA restored plasma TNF-α and IL-6 levels to near-normal values, markedly elevated IL-10, and upregulated colonic tight junction proteins ZO-1 and Occludin, reflecting a synergistic therapeutic effect combining immunomodulation and barrier repair.

Additionally, the MnCe@LR/AMs probiotic-nanozyme hydrogel microspheres developed by Zhou et al. also demonstrated notable immunomodulatory functions (Li et al., 2024). This system delivers Mn@CeO₂ nanozyme-modified Lactobacillus reuteri to colonic lesions through dual targeting of inflammatory sites by alginate microspheres (electrostatic adsorption and mannose receptor binding). In vitro experiments revealed that MnCe@LR/AMs effectively induced M2 polarization of LPS-stimulated RAW264. Seven macrophages, with a significant increase in the proportion of CD206⁺ (M2 marker) cells and a decrease in CD86⁺ (M1 marker) cells, along with reduced TNF-α and IL-1β levels and elevated IL-4 and IL-10 levels. In DSS-induced colitis mice, this hydrogel similarly confirmed its capacity to modulate macrophage polarization in vivo.

Wen et al. leveraging thrombin-mediated fibrinogen polymerization, constructed a HA-SH-Ag-Fn@bFGF@ALG biomimetic hydrogel (Wen et al., 2023). Following rectal enema administration, this hydrogel forms an adhesive artificial mucosa in situ at ulcerative sites. Through direct interaction between the fibrin scaffold and TLR4 on the surface of M1 macrophages, it inhibits downstream NF-κB signaling pathway activation (as evidenced by significantly reduced p-IKKα/β, p-IκBα, and nuclear p65 levels), thereby effectively inducing M1-to-M2 phenotypic polarization. Flow cytometry analysis revealed that the CD206⁺ M2 marker increased from 1.45% to 28.8%, while the iNOS⁺ and CD86⁺ M1 markers decreased from 70.9% and 68.2% to 48.8% and 44.2%, respectively. Concurrently, sustained release of Ag⁺ from the hydrogel eradicated local pathogenic bacteria (with inhibition rates >90% against both Escherichia coli and Staphylococcus aureus), creating favorable conditions for immune microenvironment remodeling; sustained release of bFGF and ALG synergistically promoted epithelial migration and mucosal regeneration. In the DSS-induced colitis mouse model, this hydrogel significantly reduced the disease activity index (DAI) score and myeloperoxidase (MPO) activity, restored colonic length and crypt architecture, and upregulated ZO-1 and Occludin expression. By simultaneously intervening in three pathological facets—immune activation, dysbiosis, and barrier injury—this hydrogel achieved systemic remodeling of intestinal homeostasis in IBD.

Hydrogels not only serve as passive carriers for drugs but also actively deliver immunomodulatory agents precisely to lesions through targeted delivery, controlled release, and microenvironment-responsive functionalities, thereby maximizing therapeutic efficacy (Xie et al., 2026). Notably, the immunomodulatory functions of these hydrogel systems often synergize with barrier repair and microbiota modulation. For instance, the antimicrobial action of Ag⁺ in HAMs sets the stage for their immunomodulatory effects; the ROS-scavenging capability of MnCe@LR/AMs provides a favorable microenvironment for M2 polarization; and the barrier-restoring effect of CUR/EMO NE@SA consolidates its anti-inflammatory action. This multi-target synergy represents the core advantage of hydrogels over conventional monotherapies. Future efforts should focus on developing intelligent hydrogels capable of dynamically modulating immune responses according to disease stage, and exploring combination strategies with other immunotherapeutic modalities, with the aim of further enhancing the precision and clinical benefit of IBD immunotherapy.

5 Conclusions and prospect

Stimuli-responsive hydrogels have emerged as a transformative platform for precision IBD therapy, leveraging their capacity to hierarchically navigate gastrointestinal barriers, recognize colonic inflammatory signals, and achieve spatiotemporally controlled drug release (Li et al., 2025; Klotz and Schwab, 2005). Among the established responsive mechanisms, pH-responsive systems exploit the gastro-colonic pH gradient for site-specific release, yet suffer from limited specificity and inter-individual pH variability; temperature-responsive hydrogels enable facile in situ gelation via body heat but lack active inflammatory targeting (Eyigor et al., 2018); ROS-responsive systems harness the 10- to 100-fold elevated oxidative gradients at inflamed foci, affording high microenvironmental selectivity alongside intrinsic antioxidant effects, though their synthetic complexity and heterogeneous in vivo responsiveness remain challenging (Vu et al., 2023); enzyme-responsive designs capitalize on locally overexpressed MMP-9 and esterases to achieve disease-activity-matched release, while facing substantial patient-to-patient variability and potential immunogenicity of peptide motifs (Wang et al., 2019). In parallel, fabrication methodologies critically determine the translational feasibility of these systems: emulsification offers operational simplicity and scalability but suffers from broad size distribution and solvent residuals; electrospray provides mild processing conditions and high encapsulation efficiency (40%–91%) yet is limited by low throughput; droplet microfluidics stands out for its unparalleled monodisperses (CV < 3%), structural programmability (core–shell, multi-compartment, Janus architectures), and superior bioactive preservation, positioning it as the most promising route for multifunctional hydrogel construction (Tapia-Hernández et al., 2015). At the therapeutic level, these delivery systems orchestrate intestinal homeostasis restoration through four synergistic pathways barrier repair (physical shielding or tight-junction modulation), ROS scavenging (nanozyme-mediated or responsive-moiety-based), immunoregulation (M1-to-M2 macrophage polarization via NF-κB/MAPK inhibition) (Wu et al., 2023), and microbiota modulation (probiotic–hydrogel co-delivery). By concurrently intervening at multiple nodes within the pathogenic circuitry dysbiosis, immune activation, inflammatory exacerbation, and barrier disruption, hydrogel platforms achieve true pathological loop blockade, a capability fundamentally distinct from single-target pharmacological approaches (Chakrapani et al., 2022).

Despite considerable preclinical progress, the clinical translation of stimuli-responsive hydrogels for IBD therapy remains constrained by the lack of large-animal pharmacokinetic and toxicological data, the absence of standardized scalable manufacturing protocols, and insufficient integration of real-time diagnostic feedback into current hydrogel designs (Nassar and Kasapis, 2023; Kilic Boz et al., 2022). The key challenges in clinical translation, poor colonic bioavailability, systemic side effects, and insufficient lesion-specific retention, can be effectively addressed by combining existing drugs with rationally designed responsive hydrogel carriers. For instance, pH- and enzyme-responsive hydrogel systems have been successfully employed to deliver mesalazine or budesonide specifically to the inflamed colon, significantly reducing systemic exposure and enhancing local therapeutic efficacy in preclinical models (Geng et al., 2025; Hao et al., 2023). By repurposing approved drugs within responsive carriers, the translational pathway can be substantially shortened, as this strategy leverages the well-characterized safety and efficacy profiles of existing therapeutics while overcoming their inherent limitations, thereby offering a pragmatic and accelerated route toward clinical implementation. Overcoming these barriers will require focused efforts across several interconnected domains (Zhang et al., 2018). First, the development of multi-responsive systems that synergistically integrate pH, temperature, ROS, and enzyme sensitivity is essential to achieve hierarchical programmed delivery, encompassing sequential gastric protection, colonic localization, and lesion-triggered drug release (Liu R. et al., 2024; Rommel et al., 2022). Concurrently, advances in microfluidic fabrication, augmented by high-throughput parallelization and three-dimensional printing, hold the key to producing personalized hydrogel formulations with precisely tailored size, morphology, and release kinetics (Si et al., 2024). A third priority lies in incorporating diagnostic modules such as fluorescent probes, MRI contrast agents, or PET tracers into hydrogel carriers, thereby establishing theragnostic platforms capable of coupling real-time inflammatory monitoring with closed-loop therapeutic adjustment (Liu et al., 2026). Finally, systematic evaluation of hydrogel safety, efficacy, and manufacturing reproducibility in large-animal models, together with the establishment of industry-compliant quality standards, is imperative to bridge the persistent gap between benchtop innovation and clinical application (Lu et al., 2024). Ultimately, successful translation of this technology will require convergent efforts across materials science, microengineering, immunobiology, and regulatory science, a multidisciplinary endeavor essential for transforming stimuli-responsive hydrogels into tangible therapeutic benefits for the millions of patients living with IBD worldwide.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Footnotes

Edited by: Enbo Zhu, University of California, Los Angeles, United States

Reviewed by: Zongjun Mou, Case Western Reserve University, United States

Haochen Nan, University of California, Los Angeles, United States