A Watermelon‐Like Micro/Nano Hierarchical Delivery Platform for Ulcerative Colitis by Regulating Redox Homeostasis and Remodeling Gut Microbiota

Ulcerative colitis (UC) is a refractory inflammatory bowel disease marked by mucosal barrier damage, immune dysregulation, and microbial imbalance. Current treatments are limited by systemic toxicity and inadequate targeting. Drawing inspiration from the "watermelon seed and watermelon" concept, this study employs microfluidic technology to encapsulate chondroitin sulfate (CSU) based nanoparticles (NPs) loaded with the antioxidant quercetin (Qu@CSCP) within hyaluronic acid/calcium alginate (HACM) hydrogel microspheres. This process yields a "watermelon-like" micro/nano hierarchical hydrogel microsphere system (QC@HACM) specifically designed for targeted combination therapy of UC. The HACM shell protects Qu@CSCP from the harsh gastrointestinal (GI) environment and enables targeted accumulation in inflamed colon tissue. Owing to its colon-adhesive properties, QC@HACM enhances the expression of tight junction proteins and reshapes the gut microbiota, enriching beneficial probiotics. Upon localized release, Qu@CSCP NPs activate the Nrf2/HO-1 antioxidant pathway, induce M2 macrophage polarization, and modulate the Bax/Bcl-2 ratio to suppress epithelial apoptosis. This dual mechanism effectively relieves oxidative stress and promotes mucosal healing. The therapeutic efficacy of these microspheres was further validated in a murine model of UC, as evidenced by reduced levels of pro-inflammatory cytokines accompanied by restoration of gut microbiota homeostasis. Consequently, this oral delivery platform represents a promising stepwise therapeutic strategy for comprehensive UC management.