Bacteria extracellular vesicles derived from <i>Lactobacillus reuteri</i> delivering intrinsic miR-21a-5p to accelerate diabetic wound healing

Diabetic wounds are serious complications of diabetes. They are hard to heal due to the persistently hyperglycemic and hypoxemic wound microenvironment, disturbing the angiogenesis and compromising the re-epithelialization. With the highlight of gut-skin axis that is mediated by gut microbiota and their metabolites in regulating skin hemostasis, bacterial extracellular vesicles (BEVs) secreted by probiotics are being gradually exploited as the next generation of therapeutics for diabetic wound healing. Despite their remarkable healing efficacies, the underlying molecular mechanisms remain ambiguous. Herein, BEVs derived from <em>Lactobacillus reuteri</em> (LR-BEVs) were first isolated and sequenced. With the miR-21a-5p being identified as the primary inherent component, the LR-BEVs were subsequently demonstrated to be capable of delivering it into both endothelial and epidermal cells. Consequently, the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVEC), as well as the proliferation and migration of human skin keratinocytes (HaCaT) were found to be promoted via the miR-21a-5p activated PI3K/AKT signaling pathway. In diabetic mice with full-thickness wound, the vascularized granulation tissue formation and re-epithelialization were expedited, while the inflammation was mitigated with the subcutaneous LR-BEVs treatment for 14 days. Timely diabetic wound closure was achieved without any obvious toxicity. These results envisioned the great potential of LR-BEVs as an alternative therapeutic modality for the effective and safe management of diabetic wounds.