Mitigating Environmental Pollutant-Induced Premature Ovarian Insufficiency by Rationally Designed Ultrasmall Gold Nanoparticles via Dual Regulation of ROS and Mitophagy

High Resolution Image Download MS PowerPoint Slide Premature ovarian insufficiency (POI), often induced by environmental pollutants such as 4-vinylcyclohexene diepoxide (VCD), is a growing clinical concern, with limited treatment options. Here, we report a nanotherapeutic strategy using a rationally designed ultrasmall gold nanoparticle templated with reduced glutathione (GGNP). GGNPs effectively alleviate VCD-induced granulosa cell aging through scavenging mitochondrial reactive oxygen species and activating mitophagy. This concomitant effect restores mitochondrial function and prevents mitochondrial DNA release, thereby suppressing the downstream STING-mediated senescence-associated secretory phenotype (SASP) pathway. In a VCD-induced POI mouse model, GGNP administration significantly reverses both ovarian and uterine atrophy, normalizes follicle-stimulating hormone levels, and inhibits SASP signaling without detectable toxicity. Our study thus establishes GGNP as a promising nanomedicine for environmental pollutant-induced POI by restoring mitochondrial homeostasis.