Digitonin‐Loaded Nanoscale Metal–Organic Framework for Mitochondria‐Targeted Radiotherapy‐Radiodynamic Therapy and Disulfidptosis
Year: 2024
Type: article
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.
Source: Advanced Materials
Institution: University of Chicago
Language: English
Subfield: Biomedical Engineering
Field: Engineering
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $5,780
Awards: G1755622664, G1945244547, Nanoscale Metal-Organic Frameworks Enable Radiotherapy-Radiodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Generate Tumor Vaccines and Potentiate Immunotherapy of Head and Neck Cancers, G4559543803, G4571112513, G5739243289, G6284950015, G9000074346, G9000099858, G9000133030
OpenAlex ID: W4402394791