A Copper/Ferrous‐Engineering Redox Homeostasis Disruptor for Cuproptosis/Ferroptosis Co‐Activated Nanocatalytic Therapy in Liver Cancer

Abstract Cuproptosis and ferroptosis hold great promise for overcoming apoptotic resistance in liver cancer based on their unique metal‐driven cell death modalities. However, insufficient intracellular copper and iron concentration, complicated tumor microenvironment (TME), and unclear cross‐regulatory mechanisms between cuproptosis and ferroptosis, severely restrict the therapeutic performance. Herein, copper‐doped hollow Prussian blue (CHP) nanozymes are rationally designed for loading photosensitizer indocyanine green (ICG) and O 2 ‐saturated perfluorohexane (PFH), denoted as O 2 ‐PFH@CHPI nanoparticles, to induce cuproptosis and ferroptosis. In response to the specific TME, the CHP nanozymes can synergistically catalyze Fenton reactions and consume endogenous glutathione, leading to the accumulation of reactive oxygen species. Upon near‐infrared irradiation, the O 2 ‐PFH@CHPI‐enabled photothermal effect can simultaneously accelerate catalytic reactions and trigger O 2 release for photodynamic therapy to promote oxidative stress. Notably, cuproptosis can be effectively activated through Cu + ‐mediated dihydrolipoamide S‐acetyltransferase aggregation and Fe–S cluster protein loss. Concurrently, the tilt of redox balance is favorable for lipid peroxidation and glutathione peroxidase 4 inactivation, resulting in an augmented ferroptosis effect. Mechanistically, oxidative stress‐boosted cuproptosis and ferroptosis jointly disrupt mitochondrial metabolism, which in turn exacerbates intracellular oxidative stress, thus realizing a mutually enhanced therapeutic effect. This work may provide new guidance for utilizing copper/ferrous‐engineering nanozymes for cuproptosis/ferroptosis synergetic therapy.