Identification of genetically engineered strategies to manipulate nano-platforms presenting immunotherapeutic ligands for alleviating primary ovarian insufficiency progression.

Primary ovarian insufficiency (POI) is a pathological condition characterized by the early loss of functional ovarian follicles, leading to infertility and systemic consequences affecting reproductive, skeletal, cardiovascular, and neurocognitive helath. Aberrant immune activation, particularly an augmented T cell response in the ovary, plays a critical role in POI pathogenesis. In this context, therapeutic modulation of immune responses through immune checkpoint ligands has garnered interest. In the present study, we identified Lamp2b as an optimal scaffold for engineering extracellular vesicles (EVs). By genetically modifying HEK-293 T-derived EVs to present PD-L1 and Gal-9, enabling them to suppress ovarian autoreactive T lymphocytes and protect ovarian cells from immune-mediated destruction. Functionally, the bioengineered nanoplatform demonstrated potent immunosuppressive effects by promoting apoptosis of effector T cells, reducing intraovarian CD8⁺ T cell infiltration and reinstating serum anti-Müllerian hormone (AMH) levels in POI models. These combined actions effectively halted disease progression, ultimately preventing POI progression and preserving ovarian function.