ROS-responsive small-molecule self-assembled nanocarrier-integrated hydrogels for ulcerative colitis treatment

Ulcerative colitis (UC) has a multifactorial pathogenesis, driven primarily by excessive accumulation of reactive oxygen species (ROS), aberrant inflammatory activation, intestinal barrier dysfunction, and intestinal microbiota dysbiosis. Conventional therapies face challenges including poor targeting specificity, low delivery efficiency, insufficient barrier repair, and limited microbiota modulation. Therefore, developing an intelligent drug delivery system that integrates precise targeting with ROS-responsive release is critical for effective UC treatment. Here, an ROS-responsive small-molecule self-assembled nanocarrier-integrated hydrogel (HA/MPC@B) was developed for comprehensive UC treatment. HA/MPC@B was prepared by loading berberine (BBR) into D-mannose-pinacol 4-hydroxyphenylborate-1,1'-carbonyl diimidazole (MPC) self-assembled nanoparticles, followed by their incorporation into a hyaluronic acid-hyaluronic acid methacrylate (HA-HAMA) hydrogel. Pathological levels of ROS triggered the cleavage of boronic ester bonds of MPC, enabling spatiotemporally controlled BBR release, while the hydrogel prolonged drug retention at lesion sites through local physical barrier effects. In vitro assays demonstrated the biocompatibility, ROS-scavenging capacity, macrophage polarization modulation, and anti-inflammatory and barrier-repair functions of HA/MPC@B. In vivo studies using UC models confirmed its efficacy in alleviating clinical symptoms, repairing mucosal damage, and partially restoring microbiota balance. Transcriptome analysis further revealed that HA/MPC@B reversed dextran sulfate sodium-induced dysregulation in the expression of inflammation-suppressor genes and tight junction-related genes. Overall, HA/MPC@B achieved effective UC treatment through the synergistic effects of targeted delivery, ROS-responsive release, anti-inflammatory/antioxidant activities, barrier repair, and microbiota modulation.