Nanomaterials reshaping cancer radiotherapy: Radiosensitization mechanisms, delivery and theranostic platforms, multimodal synergy, and clinical translation strategies

Radiotherapy (RT) remains a cornerstone of cancer management but is fundamentally constrained by normal tissue toxicity, intrinsic and acquired radioresistance, and hypoxia- and microenvironment-driven dose-response plateaus. Engineered nanomaterials offer a versatile toolbox to reshape this therapeutic landscape by coupling enhanced energy deposition with microenvironmental and biological reprogramming. This review summarizes recent advances in nanomaterial-enabled radiosensitization from four interlocking dimensions: (i) high-atomic-number platforms that amplify local dose via photoelectric and related interactions and thereby increase microscopic energy deposition; (ii) chemical radiosensitization through modulation of reactive oxygen species (ROS), including Fenton/Fenton-like catalysis and depletion of glutathione (GSH)/thioredoxin antioxidant networks; (iii) tumor microenvironment (TME) remodeling strategies that alleviate hypoxia, buffer acidity, rewire redox and metabolic states, relieve immune suppression, and normalize vasculature and extracellular matrix (ECM) to broaden the effective therapeutic window; and (iv) biological radiosensitization targeting DNA damage response (DDR), cell-cycle redistribution, and multiple programmed cell-death pathways such as apoptosis and ferroptosis. We further discuss nano-delivery architectures-passive EPR-based systems, ligand-directed and biomimetic carriers, and stimuli-responsive (pH, hypoxia, redox, or irradiation triggered) formulations-that co-load radiosensitizers, chemotherapeutics, and molecularly targeted agents, as well as theranostic platforms integrating computed tomography (CT)/magnetic resonance imaging (MRI)/optical contrast for image-guided, dose-adapted treatment. Emerging multimodal regimens, including radiotherapy combined with photothermal, sonodynamic, chemotherapy, and immunotherapy on a single nano-platform, are highlighted for their capacity to achieve genuine "1 + 1>2" synergy. Finally, we outline key translational challenges-industrial-scale, standardized manufacturing; long-term safety and clearance; inter-patient and spatiotemporal heterogeneity; quantitative linkage between imaging signals, dose, and biological effect; and the integration of biomarkers and artificial intelligence into personalized nano-radiotherapy-and propose future directions to accelerate clinical implementation.