Nano formulated daidzein and genistein as a multi-targeted therapeutic strategy for letrozole-induced PCOS in rats

The common endocrine disorder characterised by metabolic abnormalities, hyperandrogenism, and ovulatory dysfunction is polycystic ovary syndrome (PCOS). Natural phytoestrogens like Daidzein and Genistein show promise in modulating PCOS-related pathologies, but their clinical utility is limited by poor bioavailability.

This study aimed to develop and evaluate nanoparticle (NP)-based formulations of Daidzein and Genistein to improve their therapeutic efficacy in a letrozole-induced PCOS rat model.

Daidzein and Genistein nanoparticles (NPs) were prepared using a single-emulsion solvent evaporation technique and optimised through a 3² full factorial design. Physicochemical characterisation included FTIR, DSC, XRD, particle size, zeta potential, and FE-SEM analyses. PCOS was induced in female Wistar rats using letrozole, followed by oral administration of combined Daidzein-Genistein nanoformulations at low (25 mg/kg) and high (50 mg/kg) doses for 35 days. Animals were divided into naïve control, PCOS control, standard treatment (Clomiphene citrate), and treatment groups. Therapeutic efficacy was evaluated by assessing oestrous cyclicity, body and ovarian weight, hormonal and lipid profiles, oral glucose tolerance, oxidative stress markers, pro-inflammatory cytokines, and ovarian histopathology.

Optimised NPs demonstrated particle sizes of 198-450 nm and >90% entrapment efficiency. NP-treated groups showed significant restoration of oestrous cycles, reduced body and ovarian weight, and normalised hormone levels (LH, FSH, E2, TTST). There were notable improvements in insulin sensitivity, glucose tolerance, and lipid profiles. Markers of oxidative stress and inflammation, such as GSH, SOD, CAT, MDA, IL-6, and TNF-α, were modulated, while antioxidant enzymes and key regulators (SIRT1, PGC-1α) were upregulated. Histopathology confirmed improved follicular architecture.

Daidzein and Genistein NPs offer a potent, multi-targeted therapy for PCOS, outperforming plain drug formulations and demonstrating efficacy comparable to standard treatment. Nanotechnology-based delivery significantly enhances the bioefficacy of natural isoflavones, supporting their potential in PCOS management.