Bioengineered extracellular vesicles presenting PD-L1 and Gal-9 to ameliorate new-onset primary ovarian insufficiency (POI)

Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by premature exhaustion of primordial follicles, which causes infertility and dysfunctions of many other organ systems including sexuality, bones, the cardiovascular system, and neurocognition. An important factor in the development of POI is immune dysregulation, which results in augmented T cell response in ovary. Thus, modulation of the ovarian infiltrated T lymphocytes by exogenous PD-L1 or Gal-9 is an ideal approach for treating POI. Herein, we genetic engineered the human umbilical cord mesenchymal stem cells (hucMSCs) derived extracellular vesicles (EVs) overexpressing PD-L1 and Gal-9, which could restrict the activity of ovarian autoreactive T lymphocytes and protect ovarian cells from destruction. Moreover, PD-L1-Gal-9 EVs prominently promoted effector T cell apoptosis in vitro, and reversed the decreased AMH in the POI mice as well as declined proportion of CD8+ T cells infiltrating the ovaries, which contributed to preventing POI progression and preserving the residual ovarian fertility.