Engineering 2D Multienzyme‐Mimicking Pyroptosis Inducers for Ultrasound‐Augmented Catalytic Tumor Nanotherapy

Abstract Overcoming apoptosis resistance is necessary to ensure an effective cancer treatment; however, it is currently very difficult to achieve. A desirable alternative for cancer treatment is the targeted activation of pyroptosis, a unique type of programmed cell death. However, the pyroptosis inducers that are efficient for cancer therapy are limited. This work reports the engineering of 2D NiCoO x nanosheets as inducers of the production of harmful reactive oxygen species (ROS), which promote intense cell pyroptosis, and that can be applied to ultrasound (US)‐augmented catalytic tumor nanotherapy. The main therapeutic task is carried out by the 2D NiCoO x nanosheets, which have four multienzyme‐mimicking activities: peroxidase‐ (POD), oxidase‐ (OXD), glutathione peroxidase‐ (GPx), and catalase‐ (CAT) mimicking activities. These activities induce the reversal of the hypoxic microenvironment, endogenous glutathione depletion, and a continuous ROS output. The ROS‐induced pyroptosis process is carried out via the ROS‐NLRP3‐GSDMD pathway, and the exogenous US activation boosts the multienzyme‐mimicking activities and favors the incremental ROS generation, thus inducing mitochondrial dysfunction. The anti‐cancer experimental results support the dominance of NiCoO x nanosheet‐induced pyroptosis. This work expands on the biomedical applications of engineering 2D materials for US‐augmented catalytic breast cancer nanotherapy and deepens the understanding of the multienzyme activities of nanomaterials.