Novel neutrophil extracellular trap-related mechanisms in diabetic wounds inspire a promising treatment strategy with hypoxia-challenged small extracellular vesicles

Neutrophil extracellular traps (NETs) have been considered a significant unfavorable factor for wound healing in diabetes, but the mechanisms remain unclear. The therapeutic application of small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) has received considerable attention for their properties. Hypoxic preconditioning is reported to enhance the therapeutic potential of MSC-derived sEVs in regenerative medicine. Therefore, the aim of this study is to illustrate the detailed mechanism of NETs in impairment of diabetic wound healing and develop a promising NET-targeting treatment based on hypoxic pretreated MSC-derived sEVs (Hypo-sEVs). Excessive NETs were found in diabetic wounds and in high glucose (HG)-induced neutrophils. Further research showed that high concentration of NETs impaired the function of fibroblasts through activating endoplasmic reticulum (ER) stress. Hypo-sEVs efficiently promoted diabetic wound healing and reduced the excessive NET formation by transferring miR-17-5p. Bioinformatic analysis and RNA interference experiment revealed that miR-17-5p in Hypo-sEVs obstructed the NET formation by targeting TLR4/ROS/MAPK pathway. Additionally, miR-17-5p overexpression decreased NET formation and overcame NET-induced impairment in fibroblasts, similar to the effects of Hypo-sEVs. Overall, we identify a previously unrecognized NET-related mechanism in diabetic wounds and provide a promising NET-targeting strategy for wound treatment.