Repair of female reproductive function by GDF-9–overexpressing extracellular vesicles via ACVR1B/SMAD2 regulation in ovarian granulosa

Aging in females is characterized by dysfunctional ovaries (DOs). While human umbilical cord mesenchymal stem cell (HucMSC)–derived extracellular vesicles (EVs) have shown promise in ameliorating DO, the mechanisms underlying their effects remain poorly understood. In this study, we investigated the therapeutic potential of growth differentiation factor 9 (GDF-9)–overexpressing EVs (GOEs) on granulosa cells. We identified the activin A receptor type 1B (ACVR1B) as a critical target for the restoration of ovarian function. Genetic modification of HucMSCs to overexpress GDF-9 resulted in the production of GOEs, which, through ACVR1B activation, induced SMAD2 phosphorylation in the nucleus, thereby rescuing ovarian function. These findings provide previously unknown insights into the mechanisms by which EVs mediate ovarian recovery and propose GOEs as a potential therapeutic strategy for the treatment of DO.