A Microenvironment‐Feedback Cascaded Hydrogel for Regenerative Repair of Infected Diabetic Wounds

ABSTRACT Infected diabetic wound repair is hindered by a hostile microenvironment of heavy bacterial burden, persistent oxidative stress, toxin‐driven inflammation, and hypoxia. Here we report a microenvironment‐feedback cascaded hydrogel, termed HL‐10, for infected diabetic wound repair. HL‐10 is formed via dynamic Schiff base crosslinking between L‐arginine ‐modified chitosan and aldehyde‐functionalized F127, with erythrocyte membrane‐hybridized, polymyxin B‐modified and perfluorohexane (PFH)‐loaded liposomes (Rφ‐PLipo‐PFH) embedded within the hydrogel network. The chitosan‐based network first suppresses bacterial growth and biofilm formation. As the acidic and reactive oxygen species (ROS)‐rich conditions trigger matrix degradation, the hydrogel scavenges local ROS and generates nitric oxide to alleviate oxidative stress and inflammation. This degradation process simultaneously exposes the embedded liposomes, which neutralize bacterial toxins and reduce the LPS‐induced M1 macrophage phenotype, while the PFH core provides a sustained oxygen supply to counter hypoxia. In a Pseudomonas aeruginosa ‐infected diabetic model, HL‐10 treatment accelerated wound repair and was accompanied by attenuation of AGE‐RAGE/PI3K‐Akt signaling, restoration of angiogenesis, and improved tissue remodeling, demonstrating a systematic biomaterial approach for managing refractory wounds.