Synergistic antibacterial and anti-inflammatory potentials of dual-loaded self-healing hydrogel for methicillin-resistant Staphylococcus aureus-infected wound healing

The emergence of drug-resistant bacterial infection and persistent biofilm colonization pose a rigorous challenge to effective wound healing and regeneration, necessitating the innovative therapeutic strategies to combat these pressing clinical crises. Herein, nortriptyline, a novel FDA-approved tricyclic antidepressant was uncovered to effectively potentiate bactericidal activities of β- lactam antibiotics against methicillin-resistant Staphylococcus aureus (MRSA). Mechanistically, nortriptyline functions by disrupting the microbial iron homeostasis and potentiation of Fenton chemistry-mediated oxidative stress, concomitant with metabolic reprogramming via TCA cycle dysregulation and membrane destabilization. To enhance combination therapy-mediated therapeutic potential in wound management, the dual-loaded self-healing hydrogel OHA-PLL@AN was engineered to exhibit excellent biocompatibility and antibacterial potentials through molecular cross-linking of oxidized hyaluronic acid (OHA) and ε-polylysine (PPL). The therapeutic efficacy of OHA-PLL@AN was further validated in a murine model with MRSA-infected cutaneous wounds. OHA-PLL@AN therapy significantly attenuated the inflammatory response, concurrently promoting angiogenesis and accelerating the cutaneous wounds healing. Collectively, these findings underscore the dual drug-loaded self-healing hydrogel OHA-PLL@AN with anti-infection and anti-inflammatory properties as a novel therapeutic strategy for drug-resistant bacterial infected wounds therapy.