Abstract

We engineered HGF-overexpressing MSC-derived EVs that boost angiogenesis and shift macrophages toward anti-inflammatory M2 phenotype. • CP05-modified hyaluronic acid microcarriers capture EVs specifically and sustain their release, extending EV retention in wound tissue. • This EV-microcarrier system accelerates diabetic wound repair via collagen deposition, angiogenesis and inflammation resolution for refractory wound therapy. Extracellular vesicles (EVs) are potential valuable for refractory wounds (RWs) healing, while their treatment outcomes are unsatisfactory due to the variations among patients with different underlying disease. Here, we present a novel peptide integrated hyaluronic microcarriers for functional EVs enrichment and RWs treatment. The EVs with high-expressing hepatocyte growth factor (HGF) were derived from lentivirus-mediated gene transfection mesenchymal stromal cell (MSC). As the hyaluronic acid methacrylate was covalently conjugated with a peptide CP05 that could specifically capture EVs, the resultant microcarriers possessed excellent biocompatibility, specific EVs binding capacity and sustained release ability on the damaged skin surface. Therapeutic efficiency in the treatment of diabetic mice model with wounds demonstrated that by loading MSC HGF EVs into these functional microcarriers through percutaneous administration, they could anchor to the area of the damaged lesion. Quantitative results confirm that this treatment effectively downregulates local inflammation and accelerates wound closure rate by a large margin, achieving superior healing outcomes. Therefore, the proposed genetically engineered MSC HGF EVs and their dispersed hydrogel system for wound healing will be with high clinical potential.