Low-energy/low-dose unconventional cancer therapeutic approach using a radiosensitizing TMD-based hybrid nanosystem

Two-dimensional (2D) nanomaterials including emerging post-graphene materials such as transition metal dichalcogenides (TMDs) have shown promising potential for different biomedical applications. Owing to their high atomic number elements, large surface area, and strong optical absorption/photothermal conversion, TMD-based platforms have been successfully applied to drug delivery and multimodal therapies. Here, we present an unconventional TMD-based cancer therapeutic approach that achieves nanosystem-mediated radiosensitization in the low-energy/low-dose X-ray irradiation regime, differing from standard radiotherapy which typically uses high-energy (1-10 MeV) X-ray beams. We designed a multicomponent inorganic-organic (hybrid) nanosystem comprising 2D WS 2 nanocrystals functionalized with gold nanoparticles and porphyrin photosensitizers and showed that it enhances low-energy (40 kV) X-ray irradiation mediated killing of human colorectal cancer cells at a dose of 2 Gy delivered in a single treatment. Monte Carlo simulations guided nanosystem optimization and predicted enhanced radiation energy deposition within tumor tissues. Transmission electron microscopy combined with energy-dispersive X-ray spectroscopy confirmed cellular uptake of the nanosystem. Moreover, its excellent biocompatibility and the absence of proinflammatory responses were demonstrated using peripheral blood mononuclear cells from healthy human donors. Finally, radiosensitization efficacy was validated in radioresistant human colorectal adenocarcinoma cells (HT-29), showing significantly increased cancer cell killing versus radiation alone. The observed effect was mechanistically explained in terms of cell cycle arrest, apoptosis, and upregulation of oxidative-stress-related genes. These findings provide proof-of-concept that low-energy, low-dose X-ray irradiation, mediated by a purpose-designed multicomponent hybrid nanosystem, is a feasible cancer cell killing modality.