Glycoengineered extracellular vesicles released from antibacterial hydrogel facilitate diabetic wound healing by promoting angiogenesis

Diabetic wounds have become a global healthcare burden owing to impaired angiogenesis and persistent infections. Extracellular vesicles (EVs) can improve diabetic wounds, though their targeting ability is limited. In this study, we investigated the performance of a novel hydrogel dressing comprised of gelatin methacryloyl, glycoengineered EVs, and polylysine in treating infected diabetic wounds. High-throughput single-cell RNA sequencing (scRNA-seq) and immunofluorescence staining revealed that E-selectin (SELE) levels were higher in diabetic wounds than in non-diabetic wounds. Mesenchymal stromal cells (MSCs) were transfected with a lentivirus containing fucosyltransferase VII (FUT7) and a CD63-P19-Nluc vector to enhance the expression of sialyl Lewis X (sLeX), the ligand of E-selectin, on the surface of EVs (s-EVs) derived from transfected MSCs (s-MSCs). s-EVs can target human umbilical vein endothelial cells (HUVECs) under lipopolysaccharide stimulation and promote the function of stimulated HUVECs in vitro. To promote and sustain the release of s-EVs, we fabricated a gelatin methacryloyl (Gel)/poly-L-lysine methacryloyl (PL)-5 hydrogel with good antibacterial ability, biocompatibility and mechanical properties. In a mouse experiment, s-EV@Gel/PL-5 exhibited excellent angiogenesis and anti-inflammatory abilities and further promoted the healing of infected diabetic wounds. Our findings demonstrated the potential of the s-EV@Gel/PL-5 hydrogel in the clinical treatment of diabetic infectious wounds.