Engineering Radiosensitizer‐Based Metal‐Phenolic Networks Potentiate STING Pathway Activation for Advanced Radiotherapy

Abstract Radiotherapy, a mainstay of first‐line cancer treatment, suffers from its high‐dose radiation‐induced systemic toxicity and radioresistance caused by the immunosuppressive tumor microenvironment. The synergy between radiosensitization and immunomodulation may overcome these obstacles for advanced radiotherapy. Here, the authors propose a radiosensitization cooperated with stimulator of interferon genes (STING) pathway activation strategy by fabricating a novel lanthanide‐doped radiosensitizer‐based metal‐phenolic network, NaGdF 4 :Nd@NaLuF 4 @PEG‐polyphenol/Mn (DSPM). The amphiphilic PEG‐polyphenol successfully coordinates with NaGdF 4 :Nd@NaLuF 4 (radiosensitizer) and Mn 2+ via robust metal‐phenolic coordination. After cell internalization, the pH‐responsive disassembly of DSPM triggers the release of their payloads, wherein radiosensitizer sensitizes cancer cells to X‐ray and Mn 2+ promote STING pathway activation. This radiosensitizer‐based DSPM remarkably benefits dendritic cell maturation, anticancer therapeutics in primary tumors, accompanied by robust systemic immune therapeutic performance against metastatic tumors. Therefore, a powerful radiosensitization with STING pathway activation mediated immunostimulation strategy is highlighted here to optimize cancer radiotherapy.