A Self‐Cascade Oxygen‐Generating Nanomedicine for Multimodal Tumor Therapy

Abstract Natural and artificial enzyme oxygen‐generating systems for photodynamic therapy (PDT) are developed for tumor treatment, yet they have fallen short of the desired efficacy. Moreover, both the enzymes and photosensitizers usually need carriers for efficient delivery to tumor sites. Here, a self‐cascade‐enhanced multimodal tumor therapy is developed by ingeniously integrating self‐cascade‐enhanced PDT with Zn²⁺‐overloading therapy. Manganese‐porphyrin (TCPP‐Mn) is chosen both as the photosensitizer and catalase (CAT) mimic, which can be encapsulated within glucose oxidase (GOx). Acid‐responsive zeolitic imidazolate framework‐8 (ZIF‐8) is applied as the carrier for TCPP‐Mn@GOx (T@G), attaining TCPP‐Mn@GOx@ZIF‐8 (T@G@Z). T@G@Z demonstrates robust anti‐tumor ability as follows: upon the structural degradation of ZIF‐8, GOx can mediate the oxidation of glucose and generate hydrogen peroxide (H₂O₂); TCPP‐Mn can catalyze H₂O₂ into O₂ for self‐cascade‐enhanced PDT; meanwhile, the released Zn²⁺ can enhance oxidative stress and induce mitochondrial dysfunction by destroying mitochondrial membrane potential; furthermore, immunotherapy can be activated to resist primary tumor and tumor metastasis. The self‐cascade‐enhanced T@G@Z exhibited its potential application for further tumor management.