Quaternized chitosan-based double-network hydrogel for oral precise delivery of Sinapic acid in ulcerative colitis therapy.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease for which effective oral colon-targeted therapies remain limited. Sinapic acid (Sin), a dietary polyphenol, has demonstrated therapeutic potential in UC due to its antioxidant and anti-inflammatory properties; however, its clinical application is hindered by poor stability and low water solubility. To address these limitations, we designed a smart macromolecular double-network hydrogel based on quaternized chitosan (QCTS) derivatives and glycyrrhizic acid (GA) self-assembled hydrogel to enhance targeted Sin delivery for UC treatment. Specifically, Sin was conjugated to QCTS via reduction-cleavable disulfide linkages and dynamically crosslinked with aldehyde-functionalized GA through Schiff-base reactions, yielding the double-network hydrogel, QSAG. QSAG demonstrated structural robustness, colon-targeting capability, and reduction-responsive drug release under inflammatory conditions, which was evidenced by swelling equilibrium within 120 min, 94.23% degradation in simulated colonic fluid within 24 h, and a cumulative Sin release of 83.66% under 10 mM GSH. In vivo imaging confirmed prolonged colonic retention of QSAG in the inflamed colon for at least 24 h and localized drug accumulation. Therapeutic efficacy was evaluated in a 3% DSS-induced UC mouse model following 5 days of treatment. Both in vitro and in vivo studies revealed that QSAG effectively alleviated colitis by suppressing oxidative stress and inflammation while promoting intestinal barrier repair. Collectively, this dual-crosslinked QSAG hydrogel, with its structural stability and inflammation-responsive drug release, represents a promising oral platform for targeted and enhanced UC therapy.