A Salidroside‐Based Radiosensitizer Regulates the Nrf2/ROS Pathway for X‐Ray Activated Synergistic Cancer Precise Therapy

Abstract The hypoxic microenvironment and radioresistance of tumor cells, as well as the delay in efficacy evaluation, significantly limit the effect of clinical radiotherapy. Therefore, developing effective radiosensitizers with monitoring of tumor response is of great significance for precise radiotherapy. Herein, a novel radiosensitizer (term as: SCuFs) is developed, consisting of traditional Chinese medicine (TCM) compounds salidroside, Cu²⁺, and hydroxyl radical (•OH) activated second near‐infrared window fluorescence (NIR‐II FL) molecules, which make the radiosensitization effect and boosted chemodynamic therapy (CDT) efficacy. The overexpressed glutathione in the tumor induces the SCuFs dissociation, allowing deep penetration of the drug to the whole tumor region. After X‐ray irradiation, salidroside inhibits the Nuclear factor erythroid 2‐like 2 (Nrf2)protein expression and blocks cells in the G2/M phase with the highest radiosensitivity, which amplifies the reactive oxygen species (ROS) generation to exacerbate DNA damage, thus achieving radiosensitization. Meanwhile, the upregulated ROS provides sufficient chemical fuel for Cu⁺‐mediated CDT to produce more •OH. NIR‐II FL imaging can monitor the •OH changes during the therapy process, confirming the radiosensitization effect and CDT process related to •OH. This study not only achieves effective radiosensitization and cascaded ROS‐mediated CDT efficacy, but also provides a useful tool for monitoring therapeutic efficacy, showing great prospects for clinical application.