Axial Sulfur‐Bridged Mo‐S‐Cu Nanozymes With an Asymmetric Local Electric Field Boosting Multi‐Enzymatic Activities for Ferroptosis‐Pyroptosis Therapy

ABSTRACT The axial coordination‐based nanozymes with asymmetric local electric field (LEF) are promising for efficient reactive oxygen species (ROS)‐mediated antitumor treatments, while normally hindered by a limited LEF upon individual coordination to adjacent atoms. Herein, an axial sulfur‐bridged Mo─S─Cu nanozymes with asymmetric LEF (A‐CuN 3 S 1 @MoS 2‐x ) was constructed based on nanoislands (NIs)‐based axial ligand‐bridging to enhance ferroptosis‐pyroptosis therapy. The S bridge between Cu atoms in CuN 3 /C nanosheets and Mo site in NIs creates a broad and enhanced LEF, which facilitates rapid electron transfer between the nanozyme and substrates, thereby regulating its enzymatic activities. Theoretical calculations reveal that the S‐bridge induces asymmetric electron‐rich redistribution along the longitudinal axis of Cu─N 3 , promoting H 2 O 2 heterolysis and O 2 desorption to enhance catalase‐like and peroxidase‐like activities. Simultaneously, Mo sites extract electrons from Cu via the S bridge, augmenting oxidase‐like activities and degrade overexpressed glutathione to avoid nontherapeutic ROS consumption. Consequently, A‐CuN 3 S 1 @MoS 2‐x induces robust ferroptosis by cytotoxic ROS accumulation and causing severe mitochondria damages, while simultaneously activating pyroptosis within the tumor region without harming normal tissues. This work demonstrates high‐efficiency ferroptosis‐pyroptosis therapy driven by multi‐enzyme catalysis via axial Mo─S─Cu coordination with an expanded asymmetric LEF, offering a novel strategy for non‐apoptotic tumor treatment.