Digitonin‐Loaded Nanoscale Metal–Organic Framework for Mitochondria‐Targeted Radiotherapy‐Radiodynamic Therapy and Disulfidptosis

Abstract The efficacy of radiotherapy (RT) is limited by inefficient X‐ray absorption and reactive oxygen species generation, upregulation of immunosuppressive factors, and a reducing tumor microenvironment (TME). Here, the design of a mitochondria‐targeted and digitonin (Dig)‐loaded nanoscale metal‐organic framework, Th‐Ir‐DBB/Dig, is reported to overcome these limitations and elicit strong antitumor effects upon low‐dose X‐ray irradiation. Built from Th 6 O 4 (OH) 4 secondary building units (SBUs) and photosensitizing Ir(DBB)(ppy) 2 2+ (Ir‐DBB, DBB = 4,4′‐di(4‐benzoato)−2,2′‐bipyridine; ppy = 2‐phenylpyridine) ligands, Th‐Ir‐DBB exhibits strong RT‐radiodynamic therapy (RDT) effects via potent radiosensitization with high‐Z SBUs for hydroxyl radical generation and efficient excitation of Ir‐DBB ligands for singlet oxygen production. Th‐Ir‐DBB/Dig releases digitonin in acidic TMEs to trigger disulfidptosis of cancer cells and sensitize cancer cells to RT‐RDT through glucose and glutathione depletion. The released digitonin simultaneously downregulates multiple immune checkpoints in cancer cells and T cells through cholesterol depletion. As a result, Th‐Ir‐DBB/dig plus X‐ray irradiation induces strong antitumor immunity to effectively inhibit tumor growth in mouse models of colon and breast cancer.