Nanoencapsulated Rutin Enhances Testicular Antioxidant Defense and Steroidogenic Gene Expression in Drug-Induced Reproductive Toxicity

Doxorubicin (DOX) is a widely used anthracycline anticancer agent, yet its clinical utility is limited by considerable off-target damage that also extends to the male reproductive tract. Rutin is a naturally occurring flavonol glycoside with well-recognized antioxidant activity; however its poor aqueous solubility and rapid first-pass metabolism limit its in vivo performance. In the present work, rutin was loaded into chitosan-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NE-RUT) and its protective effect against DOX-induced testicular toxicity was evaluated in adult male Wistar rats. Forty animals were randomly distributed into four groups (n = 8): control, DOX (3 mg/kg i.p. on days 1, 4, 7, 10), DOX plus free rutin (50 mg/kg p.o.), and DOX plus NE-RUT (equivalent rutin dose, p.o.) for 28 days. Testicular tissue was processed for biochemical analysis, real-time PCR of steroidogenic genes, and sperm parameter assessment. NE-RUT exhibited a mean hydrodynamic diameter of 142 ± 8 nm, polydispersity index of 0.18, zeta potential of −28.4 mV, and an entrapment efficiency of 86.2%. Compared with the DOX group, NE-RUT significantly restored testicular SOD, CAT and GPx activities, lowered MDA, replenished GSH, and brought serum testosterone close to control values. Importantly, NE-RUT upregulated the mRNA expression of StAR, CYP11A1, 3β-HSD, and 17β-HSD to nearly control levels and outperformed free rutin across all endpoints. Sperm count, motility, viability, and normal morphology were also markedly improved. Collectively, the data suggest that nanoencapsulation considerably enhances the protective potential of rutin and may serve as a promising adjunct strategy in chemotherapy-associated reproductive injury.