Abstract

Uterine infertility is a substantial global health challenge, imposing profound physical and emotional burdens on affected individuals, with endometrial injury being a key contributing factor. In this study, we report that platelet-derived extracellular vesicles (PEVs) exhibit remarkable regenerative potential, facilitating effective endometrial repair and improving pregnancy outcomes in both preclinical and preliminary clinical settings. Leveraging their nanoscale size and biological functionality, PEVs accumulate effectively at inflammation sites within the injured endometrium following intrauterine perfusion. Mechanistic studies showed that PEVs activate the AMPK-ULK1 pathway in macrophages, enhancing mitophagy to modulate their phenotype and reduce inflammatory secretion. This fostered an immunomodulatory microenvironment conducive to endometrial regeneration. We first provide preliminary evidence from a small-scale clinical trial on the potential of PEVs for treating infertility. Our findings, which show improved pregnancy outcomes in patients with endometrial injury, support the feasibility of this approach and justify larger studies. These findings provide critical insights into the mechanisms of PEV-driven regeneration and pave the way for the development of PEV-based therapies for endometrial repair and infertility treatment.