NaYF4:Yb/Er@Mn3O4@GOX Nanocomposite for Upconversion Fluorescence Imaging and Synergistic Cascade Cancer Therapy by Apoptosis and Ferroptosis

Abstract The cell elimination strategy based on reactive oxygen species (ROS) is a promising method for tumor therapy. However, its efficacy is significantly limited by ROS deficiency caused by H 2 O 2 substrate deficiency and up‐regulation of cellular antioxidant defense induced by high glutathione (GSH) content in tumor cells. To overcome these obstacles, a multifunctional self‐cascaded nanocomposite: glucose oxidase (GOX) loaded NaYF 4 :Yb/Er@Mn 3 O 4 (UC@Mn 3 O 4 , labeled as UCMn) is constructed. Only in tumor microenvironment, it can be specifically activated through a series of cascades to boost ROS production via a strategy of open source (H 2 O 2 self‐supplying ability). The increased ROS can enhance lipid peroxidation and induce tumor cell apoptosis by activating the protein caspase. More importantly, the nanozyme can consume GSH to inhibit glutathione peroxidase 4 (GPX4) activity, which limits tumor cell resistance to oxidative damage and triggers the tumor cell ferroptosis. Therefore, this strategy is expected to overcome the resistance of tumor to oxidative damage and achieve efficient oxidative damage of tumor. Further, degradation of the Mn 3 O 4 layer induced by GSH and acidic environment can promote the fluorescence recovery of UC fluorescent nuclear for tumor imaging to complete efficient integration of diagnosis and treatment for tumor.