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

Background

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. Main body: 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.