Synergistic Berberine/Pirfenidone-Loaded Thermosensitive Hydrogel: Integrated Antibacterial Defense Activity and Pirfenidone-Mediated Angiogenesis for Efficient Diabetic Wound Repair

Abstract

Diabetic infected wounds (DIWs) represent a global healthcare burden owing to impaired angiogenesis and persistent infections. Conventional interventions typically target a single pathogenic factor, and the short residence time of free drugs within the wound bed further limits their bioavailability. In this study, we constructed an injectable thermosensitive hydrogel (CPP) based on poloxamer and chitosan, coloading berberine (BBR) and pirfenidone (PFD) to achieve combinatorial antibacterial and proangiogenic functions. CPP@(BBR + PFD) achieved sustained dual-drug release, with the gel matrix showing prolonged residence at the injection site and reduced systemic exposure. Mechanistically, BBR eliminated pathogenic bacteria, an activity previously attributed to disruption of bacterial membrane integrity, thereby removing the infectious initiator of the inflammatory cascade. PFD concurrently inhibited the inflammatory response, promoted angiogenesis and collagen deposition, and accelerated the progression from inflammation to tissue remodeling. CPP@(BBR + PFD) significantly accelerated wound closure (89.2% ± 1.9% on day 13), reduced bacterial burden, and improved tissue regeneration quality. Our findings demonstrate that rationally engineered multifunctional hydrogels can overcome pathological barriers to diabetic wound repair, offering a minimally invasive and efficient therapeutic platform for chronic diabetic wounds.