Multi-Enzyme Co-Expressed Nanomedicine for Anti-Metastasis Tumor Therapy by Up-Regulating Cellular Oxidative Stress and Depleting Cholesterol

Tumor cells movement and migration are inseparable from the integrity of lipid rafts and the formation of lamellipodia, and lipid rafts are also a prerequisite for the formation of lamellipodia. Therefore, destroying the lipid rafts is an effective strategy to inhibit tumor metastasis. Herein, a multi-enzyme co-expressed nanomedicine: cholesterol oxidase (CHO) loaded CoPN3 single-atom nanozyme (CoPN3 SA/CHO) that can up-regulate cellular oxidative stress, disrupt the integrity of lipid rafts, and inhibit lamellipodia formation to induce anti-metastasis tumor therapy, is developed. In this process, CoPN3 SA can catalyze oxygen (O2) and hydrogen peroxide (H2O2) to generate reactive oxygen species (ROS) via oxidase-like and Fenton-like properties. The doping of P atoms optimizes the adsorption process of the intermediate at the active site and enhances the ROS generation properties of nanomedicine. Meantime, O2 produced by catalase-like catalysis can combine with excess cholesterol to generate more H2O2 under CHO catalysis, achieving enhanced oxidative damage to tumor cells. Most importantly, cholesterol depletion in tumor cells also disrupts the integrity of lipid rafts and inhibits the formation of lamellipodia, greatly inhibiting the proliferation and metastasis of tumor cells. This strategy by up-regulating cellular oxidative stress and depleting cellular cholesterol constructs a new idea for anti-metastasis-oriented cancer therapy strategies. Tumor invasion and metastasis are the main causes of death in cancer patients. To overcome the limitations of current anti-tumor metastasis therapy, a novel multiple-enzymes co-expressed cholesterol oxidase loaded CoPN3 single-atom nanozyme that can destroy the lipid raft structure and inhibiting lamellipodia formation through a cholesterol depletion and oxidative stress up-regulation strategy, effectively inhibiting tumor growth and metastasis, is constructed.image