A Biomimetic Copper‐Caffeic Acid Nanozyme Activates Cuproptosis and Pyroptosis by Mimicking the Neutrophil Enzymatic Cascade

Neutrophils combat tumors through a distinct enzymatic cascade involving superoxide dismutase (SOD) and myeloperoxidase (MPO), a biocatalytic mechanism that offers a promising platform for novel antitumor strategies. However, the clinical translation of natural enzymes is hindered by inherent limitations, including poor stability and high immunogenicity. In this context, nanozymes have emerged as advanced tools for tumor therapy, with the development of cascade catalytic nanosystems representing a major research frontier. This study designed multifunctional copper-caffeic acid metal-phenolic networks (Cu-CA MPNs). Upon lysosomal entry, the nanozyme mimics the neutrophil's SOD-MPO cascade to continuously generate substantial reactive oxygen species (ROS), notably hypochlorous acid (HOCl). This process directly damages lysosomes, promotes mitochondrial ROS accumulation, and upregulates the expression of GSDMD-N and GSDME-N, ultimately triggering pyroptosis. Simultaneously, Cu-CA MPNs released from ruptured lysosomes cause abnormal copper ion accumulation within mitochondria. This enhances oligomerization of the DLAT protein and downregulates key metabolic proteins-including ACO2, ETFDH, LIAS, and FDX1-thereby inducing cuproptosis. In a tumor-bearing mouse model, Cu-CA MPNs demonstrated potent antitumor efficacy and favorable biosafety. This work provides a new perspective for tumor catalytic therapy using nanozymes that simulate the neutrophil enzymatic cascade.