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

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-CuN3S1@MoS2-x) was constructed based on nanoislands (NIs)-based axial ligand-bridging to enhance ferroptosis-pyroptosis therapy. The S bridge between Cu atoms in CuN3/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─N3, promoting H2O2 heterolysis and O2 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-CuN3S1@MoS2-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.