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

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.