Injectable Nanocomposite Hydrogel with Synergistic Biofilm Eradication and Enhanced Re-epithelialization for Accelerated Diabetic Wound Healing

Diabetic wounds remain a critical clinical challenge due to their harsh microenvironment, which impairs cellular function, hinders re-epithelialization and tissue remodeling, and slows healing. Injectable nanocomposite hydrogel dressings offer a promising strategy for diabetic wound repair. In this study, we developed an injectable nanocomposite hydrogel dressing (HDL@W379) using LAP@W379 nanoparticles and an injectable hyaluronic acid-based hydrogel (HA-ADH-ODEX). This dressing provided a sustained, pH-responsive release of W379 antimicrobial peptides, effectively regulating the wound microenvironment to enhance healing. The HDL@W379 hydrogel featured multifunctional properties, including mechanical stability, injectability, self-healing, biocompatibility, and tissue adhesion. In vitro, the HDL@W379 hydrogel achieved synergistic biofilm elimination and subsequent activation of basal cell migration and endothelial cell tube formation. Pathway analysis indicated that the HDL@W379 hydrogel enhances basal cell migration through MEK/ERK pathway activation. In methicillin-resistant Staphylococcus aureus (MRSA)-infected diabetic wounds, the HDL@W379 hydrogel accelerated wound healing by inhibiting bacterial proliferation and promoting re-epithelialization, regenerating the granulation tissue, enhancing collagen deposition, and facilitating angiogenesis. Overall, this strategy of biofilm elimination and basal cell activation to continuously regulate the diabetic wound microenvironment offers an innovative approach to treating chronic wounds.