Enhancing the sensitivity of radiotherapy in non-small cell lung cancer through nanotechnology-mediated reactive oxygen species generation

Radiotherapy (RT) is the cornerstone treatment for non-small cell lung cancer (NSCLC); however, the intrinsic radiation resistance of NSCLC and the inherent limitations of RT frequently lead to suboptimal therapeutic outcomes and poor clinical prognoses. RT primarily eliminates tumors by generating reactive oxygen species (ROS), which trigger oxidative cell death. Exogenous ROS-inducing agents can amplify this effect by exceeding the oxidative stress threshold in cancer cells, potentially enabling dose reduction and minimizing damage to surrounding healthy tissue. Despite this potential, conventional ROS inducers are hampered by poor solubility, low targeting specificity, and systemic toxicity, all of which limit their clinical applicability. Recent advances in nanomedicine have facilitated the development of nanotechnology-based strategies for ROS generation, offering promising alternatives to overcome these limitations. This review elucidates the mechanisms of ROS-mediated cell death and identifies key targets within the redox homeostasis network. It also evaluates therapeutic strategies for modulating these targets and highlights the advantages of nanodelivery systems, focusing on material properties, mechanistic insights, recent innovations, and the respective strengths and limitations of various ROS-generating nanoplatforms in radiosensitizing NSCLC. Finally, the review discusses future perspectives and outstanding challenges, providing a conceptual framework for the clinical translation of ROS-based radiosensitization strategies in NSCLC therapy.