Pericyte-derived extracellular vesicle-mimetic nanovesicles ameliorates erectile dysfunction through Lipocalin 2 in the diabetic mice

Diabetes mellitus is one of the main causes of erectile dysfunction (ED). Due to neurovascular dysfunction, men with diabetic ED do not respond well to oral phosphodiesterase 5 inhibitors. Pericyte-derived extracellular vesicles-mimetic nanovesicles (PC-NVs) are known to play a role in promoting nerve regeneration in a mouse model of cavernous nerve injury. Here, we report that administration of PC-NVs can effectively promote penile angiogenesis and neural regeneration, thereby improving erectile function under diabetic conditions. We found that PC-NVs can induce endothelial proliferation, migration, and reduce cell apoptosis under diabetic conditions. In addition, PC-NVs induce neural regeneration in STZ-induced diabetic mice in vivo and ex vivo MPG or DRG explants under high-glucose conditions. We found that Lipocalin 2 (Lcn2) is a new target of PC-NVs in this process, indicating that PC-NVs exert their angiogenesis and nerve regeneration effects by activating MAP kinase, PI3K/Akt and suppressing P53 signaling pathway in an Lcn2-dependent manner under diabetic conditions. Our findings provide new conclusive evidence that PC-NVs mediate neurovascular regeneration and erectile function recovery under diabetic conditions through an Lcn2-dependent mechanism. Local administration of PC-NVs may be a promising treatment strategy for the treatment of diabetic ED. Overall design: HG+HBS (high glucose+HBS), and HG+PC-NVs (high glucose+PC-NVs)