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

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. A self‐cascade oxygen‐generating nanomedicine TCPP‐Mn@GOx@ZIF‐8 (T@G@Z) is proposed for multimodal tumor therapy, including self‐cascade‐enhanced photodynamic therapy (PDT), Zn2+‐overloading therapy, and immunotherapy. In the acidic environment, T@G@Z releases Zn2+ and TCPP‐Mn@GOx (T@G), aggravating reactive oxygen species (ROS) levels and inducing mitochondrial dysfunction, exhibiting its potential application for tumor management.