A multifunctional self-healing polysaccharide hydrogel dual-loaded with α5E8 peptide and miRNAs for accelerating diabetic wound healing

Self-healing hydrogel formed via synergistic chemical and physical crosslinking. • Effective loading and sustained release of proteins and nucleic acids. • Multifunctional hydrogel with antioxidant and antibacterial activities. • Synergistic therapeutic effects for rapid diabetic wound repair. Diabetic wound healing is a protracted process that presents a significant clinical challenge due to impaired angiogenesis and chronic inflammation. While multifunctional hydrogels offer a promising strategy for effective wound management, achieving synergistic tissue regeneration remains a critical hurdle. In this study, an in situ forming, injectable composite hydrogel comprising methacrylated chitosan (CSMA) and dopamine-modified hyaluronic acid (HADA), crosslinked via a combination of Schiff base formation, Michael addition, and physical interactions, was developed. This platform is engineered to co-load and effectively release recombinant laminin fragment α5E8 (LM-α5E8) and pro-healing microRNAs for the synergistic acceleration of diabetic wound repair. The resulting CMHD@α5E8/miRNAs hydrogel exhibits excellent mechanical properties, intrinsic antibacterial activity, and potent antioxidant capacity, alongside confirmed in vitro hemocompatibility and cell viability, while effectively suppressing pro-inflammatory responses. In vivo evaluations using a full-thickness diabetic murine skin defect model demonstrated that this hydrogel significantly expedites wound closure. Furthermore, the delivered miRNAs optimize the wound microenvironment by silencing specific negative regulators, thereby activating essential signaling pathways to drive cellular migration and angiogenesis. Consequently, comprehensive histological and molecular validations corroborated the accelerated angiogenesis and enhanced collagen network reconstruction. Overall, this multifunctional hydrogel represents a highly effective wound dressing, offering substantial therapeutic potential for diabetic skin injury management. Download: Download high-res image (186KB) Download: Download full-size image