A Multifunctional ε-Polylysine/Hyaluronic Acid Hydrogel Promotes Diabetic Wound Healing by Orchestrating Multidimensional Synergy

Background/Objectives: Diabetic wound healing faces significant challenges due to the harsh microenvironment of wounds such as high blood glucose levels, excessive inflammation, persistent infection, upregulated reactive oxygen species (ROS), and damaged new blood vessels. Therefore, developing hydrogel dressings with microenvironmental regulation functions has become an important strategy in treating diabetic wounds. Methods: In this study, an ultraviolet in situ crosslinked hydrogel (D@H/E) was developed using methacrylic anhydride modified hyaluronic acid (HA-MA) and glycidyl methacrylate modified ε-polylysine (EPL-GMA), loaded with the iron chelating agent desferrioxamine (DFO). The physicochemical and biochemical properties of the hydrogel were comprehensively characterized, and its efficacy as a dressing for diabetic wounds was evaluated in a STZ-induced hyperglycemic mouse model. Results: This hydrogel demonstrated remarkable multidimensional effects by alleviating oxidative stress damage, inhibiting bacterial infection, regulating inflammatory responses, mitigating ferroptosis, and promoting cell migration and tubule formation. Specifically, the DFO-loaded hydrogel achieved a high DPPH radical scavenging efficiency of 80.8% and exhibited excellent antibacterial activity, with over 99.8% inhibition against both S. aureus and E. coli. In streptozotocin (STZ)-induced diabetic mice, the hydrogel accelerated wound closure to near completion by day 14. Mechanistically, it significantly upregulated CD206 expression to promote M2 macrophage polarization, upregulated the expression of angiogenesis-related factors to promote angiogenesis at the wound site, and enhanced GPX4 expression to alleviate ferroptosis. Conclusions: By orchestrating multi-dimensional synergy that combines ROS scavenging, infection control, immune regulation, and anti-ferroptosis, this D@H/E hydrogel system effectively remodels the harsh diabetic wound microenvironment, offering a promising platform for chronic wound management.