The development of metal radiosensitizers to enhance radiotherapy efficacy in cancer treatment

Radiotherapy (RT) remains the cornerstone in cancer treatment; however, radioresistance and side effects on healthy tissues often hinder RT efficacy. The advances in nanotechnology and radiobiology have propelled metal radiosensitizers as a powerful tool to overcome these obstacles in RT. The metal-based radiosensitizers enhance RT efficacy through multifaceted mechanisms, including physical energy deposition, chemical catalysis, and the generation of reactive oxygen species (ROS), as well as the modulation of biological pathways. It is like that the little hero Nezha uses a pearl to absorb X-rays, amplifying his weapons and effectively killing tumor monsters in three ways. In addition, we have discussed three major strategies of high-Z metal enhanced energy deposition, X-ray induced radiodynamic therapy (X-RDT), and Cerenkov radiation activated photodynamic therapy (CR-PDT). Here, we aim to stimulate the development of innovative, precision-driven strategies to unlock the full potential of metal-based radiosensitizers for next-generation radiosensitizations in RT. (https://doi.org/10.1002/rar2.70039)