Multifunctional BSA-Stabilized MnO ₂ –Bi ₂ S ₃ -MTX Nanoparticles for Cancer Therapy

Synergistic radiochemotherapy for breast cancer is often hindered by critical challenges, including tumor hypoxia and inherent radioresistance, which limit treatment efficacy. Overcoming these barriers requires advanced nanoplatforms capable of modulating the tumor microenvironment while precisely codelivering therapeutics. Here, we address these challenges by designing and developing a multifunctional bovine serum albumin (BSA)-stabilized MnO2–Bi2S3-Methotrexate (MTX) nanoplatform. Synthesized through a biomineralization approach, the nanoplatform exhibits a hydrodynamic diameter of 67 nm and a zeta potential of −20.9 mV, ensuring excellent colloidal stability. Experimental investigations revealed a pH-responsive MTX release profile and enhanced radiosensitization, which is attributed to the high-Z properties of Bi2S3 and the hypoxia-mitigating, oxygen-generating function of MnO2. To gain deeper mechanistic insights, computational analyses were employed: molecular docking studies confirmed MTX’s stable binding to BSA subdomains IIA and IIIA with a binding free energy (ΔG) of −14.79 kcal/mol, while density functional theory (DFT) calculations revealed a robust interaction energy of −154 kcal/mol for the MTX-α-MnO2–Bi2S3 complex, featuring a HOMO–LUMO gap of 2.56 eV and a Fermi energy of −3.74 eV (Bi2S3: −3.98 eV, MnO2: −4.41 eV), underscoring its electronic suitability for radiosensitization. Additionally, MD simulations over 10,000 ps at 310 K demonstrated structural stability with a root-mean-square deviation (RMSD) of ∼1.8–2.0 nm, dynamic flexibility with a root-mean-square fluctuation (RMSF) of ∼0.15–0.3 nm, stable hydrogen bonding (∼2–3 bonds for MTX-MnO2–Bi2S3, radial distribution function peak at ∼2.0 Å), and compactness with a radius of gyration (Rg) of ∼0.5 nm for MTX and ∼1.5 nm for MnO2–Bi2S3. These combined experimental and computational findings highlight the nanoplatform’s potential to overcome tumor hypoxia, deliver MTX effectively, and enhance radiotherapy outcomes, offering a robust and innovative framework for synergistic cancer therapy and paving the way for future preclinical development.