Thiol-mediated ROS-responsive hydrogel with arginine-driven NO cascade for colitis treatment

Developing integrated, drug-free therapeutic platforms that simultaneously address oxidative stress, immune dysregulation, and gut microbiota dysbiosis remains a significant challenge in UC management. Although hydrogels offer localized delivery advantages, their clinical versatility is frequently hindered by a reliance on exogenous drug encapsulation. To overcome this limitation, we developed a multifunctional, ROS-responsive hydrogel (ODCAS) that functions as an inherently bioactive platform. The ODCAS network is constructed via dynamic Schiff base crosslinking between ODex and thiolated arginine chitosan, further reinforced by ROS-triggered disulfide bonds leveraging. This sophisticated architecture undergoes ROS-responsive programmed degradation, driving in situ NO generation to trigger a therapeutic cascade. Specifically, the TPA-derived thiol moieties facilitate inflammation-targeted mucoadhesion via disulfide exchange with the mucosal layer, while simultaneously providing potent, direct ROS scavenging (72.21 ± 2.47% DPPH· radical scavenging). Furthermore, the metabolic byproducts of the hydrogel network provide prebiotic support to restore microbial equilibrium. In a DSS-induced murine colitis model, oral administration of ODCAS significantly attenuated disease severity, reducing the DAI by 52.08%, downregulating pro-inflammatory cytokines, and restoring both intestinal barrier integrity and microbial homeostasis. These findings highlight the ODCAS hydrogel as a robust, ROS-responsive biomaterial platform that orchestrates disulfide-mediated anchoring and an arginine-driven NO cascade for the effective management of chronic inflammatory diseases.