A Mucoadhesive Hydrogel for Precise Resveratrol Delivery in the Management of Inflammatory Bowel Disease

ABSTRACT Natural drug‐food homology compounds have vast therapeutic potential, particularly for inflammatory bowel disease (IBD), but their poor water solubility, instability, and limited mucosal availability hinder their clinical translation. As a proof of principle, the natural polyphenol resveratrol (Res) was conjugated to a disulfide‐bridged carboxymethyl chitosan (CMCS) for inclusion in a negatively charged hydrogel (CMTR‐Gel). The CMTR‐Gel was stable, with a zeta potential of approximately −37 mV in the gastrointestinal environment, and significantly inhibited reactive oxygen species production and mitochondrial depolarization in RAW 264.7 cells under lipopolysaccharide‐induced stress. The orally administrated CMTR‐Gel preferentially adhered to inflamed mucosa for 24 h through electrostatic interactions between anionic CMCS and cationic transferrin. Because of its prolonged adhesion and precise Res release at inflamed mucosa, CMTR‐Gel achieved superior therapeutic efficacy compared to the first‐line drug sulfasalazine in colitis mice, and was especially efficacious for mucosal healing through its repair of tight junction integrity. The CMTR‐Gel represents a promising strategy for the application of natural drug‐food homology compounds in the management of IBD.