Engineering MMP9-Responsive Antioxidative Micelle-Hydrogel Dressings for Sequential Inflammatory Remodeling and Pro-Angiogenesis in Diabetic Wound Healing

Chronic diabetic wounds impose substantial economic burdens, as well as physical and psychological distress, on both society and patients. Oxidative stress and upregulated matrix metalloproteinase-9 (MMP9) activity are common in chronic wounds. These wounds also exhibit insufficient angiogenesis, which inhibits the delivery of oxygen and nutrients and thereby limits wound healing. Therefore, scavenging excess reactive oxygen species (ROS) from wounds and promoting angiogenesis would synergistically promote wound healing. In this study, we prepared a hydrogel that continuously scavenges ROS and releases the pro-angiogenic drug deferasirox in an MMP9-responsive fashion. Specifically, rosmarinic acid was modified with an MMP9-responsive short peptide (Met-Gly, MG) onto polyethylene glycol end groups to create an amphiphilic molecule, designated as RA-MG-PEG. This molecule was loaded with the hydrophobic drug deferasirox using a thin-film method to form drug-loaded micelles, designated as RD. RD was then encapsulated in a polyvinyl alcohol (PVA) freeze-thaw hydrogel to form the wound dressing RD@PVA. In in vivo experiments, the RD@PVA hydrogel effectively reduced ROS levels in wound cells during the inflammatory phase, decreased the proportion of M1 macrophages, and significantly increased blood vessel density during the wound's proliferative phase. Additionally, it accelerated the wound healing rate, increased the collagen content in the wound, and promoted hair follicle regeneration, thereby effectively facilitating wound healing.