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Synthesis of berberine (BBR) and berberrubine (M1)-loaded nanostructured biloalbuminosomes (BILS) for attenuation of toxic metals-induced testicular and prostatic oxidative stress, inflammation, excessive autophagy and apoptosis that in turn negatively affect spermatogenesis and production of healthy sperm. BB: berberine; M1: berberrubine; IL-1β : interleukin 1β; IL-6 : interleukin 6; TNF-α : tumor necrosis factor-α; GST : Glutathione-S-transferase; GPx : Glutathione peroxidase; GSH : Reduced glutathione; SOD : Superoxide dismutase; NO : Nitric oxide; TBARS : Thiobarbituric acid reactive substances; LC-3II : Light chain 3-II; AMPK : AMP-activated protein kinase, P62 : Sequestosome-1; PI3K : phosphoinositide 3-kinase; mTOR : Mammalian target of rapamycin; BAX : Bcl-2-like protein 4; BCL-2 : B-cell lymphoma 2. [Display omitted] • Berberrubine was semi synthesized from berberine. • Nanostructured biloalbuminosomes (BILS) are composed of either sodium cholate or sodium glycocholate as bile salts. • Treatment of rats with the optimized BILS significantly reduced testicular and prostatic damage compared to free drug. • BILS reduced oxidative stress, inflammation, and autophagy markers, so improved infertility status in male rats. • Berberrubine loaded into BILS exhibited greater efficacy compared to Berberine in reversing male infertility. Despite the remarkable biological effects of berberine (BBR), particularly on fertility, its bioavailability is low. This study aims to test the effectiveness of novel nanostructured biloalbuminosomes (BILS) of BBR and its metabolite berberrubine (M1) in treatment of testicular and prostatic lesions. M1 was semi-synthesized from BBR using microwave-assisted reaction. The solvent evaporation method was used to prepare BBR-BILS and M1-BILS by three different concentrations of sodium cholate (SC) or glycocholate (SG), along with the incorporation of bovine serum albumin (BSA). The prepared BILS were fully characterized. Male infertility was induced by cadmium (Cd) at 5 mg/kg and lead (Pb) at 20 mg/kg contaminated water for 90 days, followed by treatment with BBR, M1, and their BILS (BBR-BILS and M1-BILS) for 45 days. Blood male infertility markers, testicular and prostatic oxidative stress status, autophagy, inflammation, along with testicular and prostatic concentrations of Cd and Pb, and histopathology of both tested tissues were determined using standardized protocols. The optimal BBR-BILS and M1-BILS nano-preparations, containing 30 mg SC, were chosen based on the best characterization properties of the preparations. Both nano-preparations improved heavy metals-induced testicular and prostatic deformities, as they reduced Bax and elevated Bcl-2 expressions in both tissues. Moreover, they activated the mTOR/PI3K pathway with a marked reduction in AMPK and activated LC-3II protein levels. Consequently, testicular and prostatic architecture and functions were improved. This study is the first to report the preparation of BBR and M1 BILS nano-preparations and proved their superior efficacy compared to free drugs against testicular and prostatic deformities by attenuating oxidative stress-induced excessive autophagy, offering a new hope to manage male infertility. [ABSTRACT FROM AUTHOR]