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, CeO 2 Mn 1.08 O x nanoclusters, is prepared. This novel Ce─Mn heterojunction is formed by oxidation of CeO 2 nanoparticles through H 2 SO 4 /KMnO 4 . CeO 2 Mn 1.08 O 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 CeO 2 Mn 1.08 O x and linked with poly(ethylene glycol) (PEG) to obtain the cascade enzyme system (Ce─Mn)‐PEI/GOx‐PEG. CeO 2 Mn 1.08 O 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, H 2 O 2 , is also used to generate O 2 and ROS. In addition, the heterojunction structure provides CeO 2 Mn 1.08 O 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 CeO 2 Mn 1.08 O x . When combining mild PTT with catalytic therapy, the cascade enzyme system (Ce─Mn)‐PEI/GOx‐PEG can efficiently ablate tumors.