A Novel Ce─Mn Heterojunction‐Based Multi‐Enzymatic Nanozyme with Cancer‐Specific Enzymatic Activity and Photothermal Capacity for Efficient Tumor Combination Therapy

Abstract Catalytic medicine, using enzymes or nanozymes, is an emerging method for cancer treatment. However, its applicability is limited by the low catalytic activity in the tumor microenvironment (TME). In this work, a versatile and synthesis‐friendly nanozyme, CeO₂Mn_1.08O_x nanoclusters, is prepared. This novel Ce─Mn heterojunction is formed by oxidation of CeO₂ nanoparticles through H₂SO₄/KMnO₄. CeO₂Mn_1.08O_x exhibits high multi‐enzymatic catalytic activities and acts as a catalase (CAT), peroxidase (POD), and oxidase (OXD) mimics under acidic conditions. It can regulate the TME by relieving hypoxia and consuming endogenous glutathione (GSH). Glucose oxidase (GOx) is then incorporated into CeO₂Mn_1.08O_x and linked with poly(ethylene glycol) (PEG) to obtain the cascade enzyme system (Ce─Mn)‐PEI/GOx‐PEG. CeO₂Mn_1.08O_x exhibits CAT‐like properties, which sensitize GOx‐based starvation therapy, and POD‐ and OXD‐like properties, which generate highly cytotoxic reactive oxygen species (ROS) in cancer cells. The glucose catabolic product, H₂O₂, is also used to generate O₂ and ROS. In addition, the heterojunction structure provides CeO₂Mn_1.08O_x with near‐infrared (NIR) photothermal capability, making it suitable for photothermal therapy (PTT). Density functional theory (DFT) calculations provide possible reasons for the high catalytic activity and photothermal capability of CeO₂Mn_1.08O_x. When combining mild PTT with catalytic therapy, the cascade enzyme system (Ce─Mn)‐PEI/GOx‐PEG can efficiently ablate tumors.