Diosgenin-loaded Silver Nanoparticles: Dual Protective Role and Enhanced Radiosensitivity against ENU-induced Leukemia and γ-irradiation-induced Liver Toxicity.

Introduction: Leukemia and radiation-induced liver toxicity are significant health challenges requiring effective therapeutic strategies. This study aimed to evaluate the therapeutic efficacy and radiosensitizing effects of Diosgenin-loaded silver nanoparticles (Dio-AgNPs) in ENU-induced leukemic mice, with a focus on their dual role in mitigating leukemia progression and γ-irradiation-induced hepatotoxicity.

Methods: Dio-AgNPs were synthesized and characterized using TEM, UV-Vis spectroscopy, FT-IR spectroscopy, and encapsulation efficiency analysis. Leukemic mice were treated with Dio-AgNPs (90 mg/kg b.w.) and γ-irradiation (2 Gy). Biological assays assessed hematological parameters, liver function, oxidative stress biomarkers, and gene expression (Nrf2, ABCC1, NQO1). Molecular docking analyzed diosgenin's binding affinities to target proteins. Histological evaluation of liver tissues and in silico ADMET profiling were also performed.

Results: Dio-AgNPs exhibited a mean diameter of 51.60 ± 1.54 nm, zeta potential of -19.5 ± 0.2 mV, and high encapsulation efficiency (84.98 ± 0.45%). Treatment significantly improved blood parameters (e.g., 39.4% increase in Hb, 41.5% reduction in WBCs), reduced liver enzymes (40.4% decrease in AST), and lowered oxidative stress (50.1% reduction in MDA). Synergy with γ-irradiation enhanced radiosensitivity (IC50: 24.55 μg/mL vs. 58.35 μg/mL alone). Molecular docking revealed strong binding to Nrf2 (-9.04 kcal/mol), ABCC1 (-10.05 kcal/mol), and NQO1 (-10.71 kcal/mol). Histology confirmed hepatoprotection, with minimal degeneration in combination-treated groups.

Discussion: Dio-AgNPs demonstrated multifaceted benefits, including anti-leukemic, antioxidant, and anti-inflammatory effects, amplified by γ-irradiation. The activation of the Nrf2 pathway and modulation of detoxification genes (ABCC1, NQO1) underpinned their therapeutic mechanism. Limitations include a single timepoint analysis and the need for human-relevant validation.

Conclusion: Dio-AgNPs are a promising dual-function therapy for leukemia and radiationinduced liver damage, combining targeted cytotoxicity with organ protection. Future research should optimize dosing and explore clinical translation.