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The current study aimed to investigate the potential of methotrexate (MTX) functionalized, 5-aminolevulinic acid (5-ALA)-modified, chitosan-coated manganese dioxide (MnO 2 /CS) nanoparticles (NPs) as a targeted radiosensitizer for cancer therapy. The novelty of the current study lies in the development of the MnO 2 /CS@5-ALA-MTX NPs as a novel formulation with high encapsulation capacity, site specificity, and biosafety for targeted drug delivery. The study also emphasizes comprehensive in-vitro tests to understand the cell death mechanisms after radiosensitization. The effects of MnO 2 /CS@5-ALA-MTX NPs on U87MG cell lines treated with radiation were examined in-vitro and in-vivo. Mitochondrial function and reactive oxygen species (ROS) production were evaluated under normoxia and hypoxia conditions. The combination of MTX and 5-ALA provided tumor-targeting ability, while the CS coating prolonged the circulation time of the nano-system. The synthesized MnO 2 /CS@5-ALA-MTX NPs had an average size of 70 ± 9 nm, a Zeta potential of −6 ± 2 mV, and a polydispersity of 0.240. The loading efficiency and release profile of the drug delivery system were assessed and demonstrated its capacity for drug delivery. The MTT assay on U87MG cells revealed that MnO 2 /CS@5-ALA-MTX NPs reduced cell viability compared to MTX alone. Both in-vitro and in-vivo studies demonstrated tumor-enhanced radiosensitization using MTX functionalized MnO 2 /CS NPs. The mice receiving MnO 2 /CS@5-ALA-MTX NPs and subsequent radiation exposure exhibited significant tumor inhibition and increased survival ratios. Notably, tumor-bearing mice treated with MnO 2 /CS@5-ALA-MTX NPs and X-ray irradiation demonstrated more effective tumor rejection compared to the groups treated with X-ray alone or NPs alone. In conclusion, the results highlight the potential of MnO 2 /CS@5-ALA-MTX NPs as a targeted radiosensitizer for cancer therapy. The NPs exhibited promising tumor-inhibiting effects and enhanced radiosensitization both in-vitro and in-vivo , suggesting their potential as a valuable approach for cancer treatment in the future. [Display omitted] [ABSTRACT FROM AUTHOR]