Metformin-Functionalized Selenium Nanoparticles Restore Insulin Signaling and Metabolic Homeostasis in Letrozole-Induced Polycystic Ovary Syndrome Rat Model.

In this study, we designed a novel 'metformin-coated nanoselenium nanocomposite' (Met+SeNP) to leverage the synergistic potential of both agents delivered via a single nanoplatform, aiming to restore metabolic and hormonal homeostasis in a letrozole-induced PCOS rat model. Met+SeNP was synthesized via a redox reaction of sodium selenite and ascorbic acid in the presence of metformin, creating a stable metformin-functionalized selenium nanocomposite. The particles were characterized using UV-Vis spectroscopy, SEM, and EDX. Female Sprague-Dawley rats were divided into five groups: Healthy, PCOS (letrozole-induced), Metformin (300 mg/kg), SeNP (0.4 mg/kg), and Met+SeNP (nanocomposite dose, SeNP 0.4 mg/kg + Metformin 300 mg/kg). The nanocomposite treatment most effectively minimized weight gain (39.36% vs. PCOS controls), normalized HOMA-IR, and restored circulating LH, estrogen, and testosterone levels. Histopathological evaluation demonstrated a marked reduction in cystic follicles and recovery of corpus luteum formation following Met+SeNP therapy. Immunohistochemical analysis further revealed that Met+SeNP robustly reversed PCOS-induced suppression of INR, IRS-1, and IRS-2 expression in both liver and skeletal muscle tissues. In addition, the nanocomposite significantly improved serum ALT, AST, and ALP levels while maintaining normal urea and creatinine concentrations, supporting hepatic protection and systemic safety. The metformin-functionalized SeNP nanocomposite represents a promising potent therapeutic strategy for PCOS-associated metabolic dysfunction, outperforming monotherapies in restoring insulin signaling, endocrine balance, and tissue integrity.