Lipid raft-targeting artificial cascade nanozyme for enhanced anti-metastatic tumor therapy by cholesterol depletion and ROS upregulation

The migratory capacity and invasiveness of tumor cells are critically dependent on two key cellular features: lamellipodia formation at the leading edge of cells and the structural integrity of lipid rafts. Within the tumor microenvironment (TME), cholesterol (Ch), a core lipid raft constituent, is frequently observed to be overabundant. Excess Ch promotes cancer cell proliferation, enhances tumor cell motility, induces epithelial-mesenchymal transition (EMT), and elicits immunosuppressive effects. However, there remains a lack of targeted and effective strategies to normalize excess Ch levels in tumor lesions. Herein, we fabricated a cascade catalytic nanozyme (CHO@Cu/His-ZIF8) via in-situ mineralization of cholesterol oxidase (CHO) within L-histidine (His)-modified Cu-ZIF8. This nanozyme not only mimics the catalytic activity of natural peroxidase (POD) to achieve self-amplified reactive oxygen species (ROS) generation (CHO oxidizes Ch to produce H₂O₂; the catalase-like activity of the nanozyme simultaneously decomposes partial H₂O₂ to generate O₂, which further accelerates Ch consumption by CHO; meanwhile, the POD-like activity converts H₂O₂ into highly toxic •OH), but also degrades excess Ch to disrupt lipid rafts and lamellipodia, thereby inhibiting tumor cell migration and invasion. In vivo studies confirmed that CHO@Cu/His-ZIF8 effectively accumulated at tumor sites and exhibited excellent biocompatibility. Experiments in subcutaneous tumor models, lung metastasis models, and bilateral tumor models consistently demonstrated that CHO@Cu/His-ZIF8 exerts potent and highly efficient antitumor efficacy, especially in inhibiting tumor metastasis, highlighting its promising clinical translation potential. Schematic representation of CHO@Cu/His-ZIF8 for combined treatment involving cholesterol depletion and ROS upregulation. Download: Download high-res image (181KB) Download: Download full-size image