Engineered‐Doping Strategy for Self‐Sufficient Reactive Oxygen Species Blossom to Amplify Ferroptosis/Cuproptosis Sensibilization in Hepatocellular Carcinoma Treatment

Abstract Ferroptosis and cuproptosis are emerging modes of programmed cell death and have been increasingly used to eliminate tumor cells. However, converting ferroptosis/cuproptosis into effective treatments is challenging because of the inherent antioxidant and plasma membrane repair systems and inefficient copper ion delivery. Herein, an engineered doping method is developed to encapsulate ZnO₂ with Cu²⁺‐doped ZIF‐8 and modify the surface by transferrin (Tf). In the resulting ZnO₂@Cu/ZIF‐8‐Tf nanosystem, Tf specifically binds to transferrin receptors for targeting and aggregation. In the tumor microenvironment, Cu²⁺/Fe³⁺ is released from the nanosystem and reacted with glutathione (GSH) to produce Cu⁺/Fe²⁺. Excessive accumulation of Cu⁺ interfered with the tricarboxylic acid cycle and induced coproptosis. Furthermore, the additional Fe²⁺ caused iron overload and enhanced ferroptosis. ZnO₂ supplied hydrogen peroxide to mediate the overproduction of reactive oxygen species (ROS). Moreover, the depletion of GSH deactivated glutathione peroxidase 4 (GPX4) and inhibited the system X_c⁻‐GSH‐GPX4 pathway, and the amplified ROS triggered lipid peroxidation and reprogrammed lipid metabolism, causing malfunctioning of both antioxidant and membrane repair systems. In summary, the ferroptosis/cuproptosis pathways are activated at multiple levels in the ZnO₂@Cu/ZIF‐8‐Tf nanosystem, which ensures its outstanding antitumor effect.