Hetero‐Trimetallic Atom Catalysts Enable Targeted ROS Generation and Redox Signaling for Intensive Apoptosis and Ferroptosis

Reactive oxygen species (ROS) play crucial roles in cellular metabolic processes by acting as primary intracellular chemical substrates and secondary messengers for cellular signal modulation. However, the artificial engineering of nanozymes to generate ROS is restricted by their low catalytic efficiency, high toxicity, and off-target consumption. Herein, hetero-trimetallic atom catalysts (TACs) anchored on a stable symmetrical pyramid structure are designed in the presence of N and P surface ligands from cross-linked polyphosphazene interlayer-coated MIL-101(Fe). The 3D network TACs with a uniform dispersion of Cu, Co, and Fe hetero-single atoms effectively tailor the active sites to avoid metal sintering, thereby providing sufficient catalytic activity for ROS blooms. Nanovesicle membranes facilitate the stable accumulation of nanozymes with homologous targeting, recognition, and endocytosis, effectively addressing the potentially high toxicity and off-target defects. Therefore, the outcome of the in situ ROS-bloom acts as a redox signal for directly regulating oxidative stress in the tumor microenvironment. Meanwhile, ROS intervene in the glutathione peroxidase 4, long-chain acyl-CoA synthetase 4, and cysteinyl aspartate specific proteinase-3 pathways as second messengers, fostering the proclivity toward apoptosis and lipid peroxidation-regulated ferroptosis pathway concurrently, thereby highlighting the application prospects of TACs in the biomedical field.