Natural Polymer-Based Hydrogels for Localized Therapy in Inflammatory Bowel Disease: From Smart Materials to Clinical...

Inflammatory bowel disease (IBD) remains difficult to manage in a substantial proportion of patients because conventional systemic therapies may fail to achieve sufficient drug accumulation at inflamed intestinal sites while causing systemic adverse effects. Therefore, localized delivery systems capable of protecting therapeutic agents during gastrointestinal transit and releasing them at disease sites are urgently needed. Natural polymer-based hydrogels have attracted increasing attention because of their biocompatibility, biodegradability, mucoadhesiveness, and tunable responsiveness to intestinal pathological cues.

This review focuses on natural polymer-based hydrogels for localized therapy in IBD. We first summarize the major drug-loading strategies, including physical encapsulation, diffusion/permeation, covalent bonding, and electrostatic interaction, as well as key release mechanisms, including stimulus-responsive, diffusion-controlled, swelling-controlled, and chemically controlled release. We then systematically discuss six widely studied natural polymer-based hydrogel systems-gelatin, hyaluronic acid, alginate, chitosan, cellulose, dextran, and their derivatives. Particular attention is given to how material composition, network architecture, and disease-responsive properties influence drug protection, mucosal retention, colon-targeted release, anti-inflammatory activity, and intestinal barrier repair. Representative preclinical and translational studies are reviewed to compare the advantages and limitations of these systems. We also highlight major formulation and translation challenges, including batch variability, insufficient mechanical stability, burst release, limited targeting precision, unpredictable in vivo degradation, and scalable manufacturing.

Natural polymer-based hydrogels provide a promising platform for localized IBD therapy by integrating biocompatible materials with controllable drug loading and disease-responsive release. Future progress will depend on disease-driven material design, rational integration of multi-responsive or composite hydrogel systems, rigorous evaluation in physiologically relevant models, and scalable manufacturing strategies. These advances may facilitate the clinical translation of personalized and locally acting hydrogel therapies for IBD.