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