Inflammatory memory-activated biomimetic nanovesicles regulate neutrophil plasticity and metabolic reprogramming for rapid diabetic wound healing via targeting miR-193a-5p/TLR4/JNK/P38 MAPK pathways

Diabetic wound therapy faces significant challenges due to the complexity of the wound microenvironment, especially dysregulated immune cell responses and persistent pro-inflammatory sate. Targeting immune cells to reverse pathological wound conditions has increasingly become a promising strategy to promote diabetic wound healing. It has been reported that prolonged memory to acute inflammation sensitizes epidermal stem cells (EpSCs) to tissue damage. The increasing importance of interactions between immune cells and tissue stem cells has raised interest in the potential of EpSCs to induce inflammatory adaptations in diabetic wounds, and meanwhile, the inflammation memory patterns also provide new insight in EpSCs for tissue repair. Here, bioinspired cell-derived mimetic nanovesicles (MNVs) were obtained from inflammation memory-activated EpSCs. LPS treatment could trigger acute inflammation response and activate inflammation memory. MNVs derived from LPS-pretreated EpSCs (LEM) can effectively promote diabetic wound healing by manipulating crucial neutrophil regulatory mechanisms. The in vitro and in vivo studies demonstrated that LEM could stimulate neutrophil mitochondrial metabolic reprogramming, overcome phenotypic switching deficiency of neutrophils, and skew neutrophils toward N2 anti-inflammatory phenotype via regulating miR-193a-5p/TLR4/ JNK/P38 MAPK pathways in diabetic models. Our findings highlighted the great potential of inflammation memory in EpSCs, and also provided an alternative for diabetic wound treatment.