Heterojunction nanozyme achieve highly efficient antibacterial by cuproptosis-like death and ferroptosis-like death

Metal-ion-mediated lethal pathways offers a highly potent strategy for antibacterial treatments. However, relying on single-pathway mechanisms often fails to overwhelm bacterial antioxidant defenses, reducing antibacterial efficacy. This study designed a heterojunction nanozyme (Cu₂O/Fe₂O₃) that induces ferroptosis-like death and copper-mediated metabolic toxicity exhibiting cuproptosis-like features, achieving highly effective antibacterial treatment. Computational chemistry analysis indicates that the Cu₂O/Fe₂O₃ heterointerface establishes a built-in electric field through spontaneous interfacial electron transfer, thereby enhancing its peroxidase (POD)-like activity. Within the acidic bacterial microenvironment, Cu₂O/Fe₂O₃ catalyzes the generation of large amounts of reactive oxygen species (ROS) and releases metal ions, inducing and amplifying ferroptosis-like death, which disrupts the function of ETC enzymes by attacking iron-sulfur clusters. Concurrently, copper ions disrupt the redox balance by depleting bacillithiol (BSH), indirectly increasing bacterial susceptibility and promoting ferroptosis-like death. Furthermore, the accumulation of copper ions triggers severe metabolic impairments that biochemically resemble the cuproptosis cascade, which disrupts key enzymes of the TCA cycle and impairs the synthesis of electron donors (NADH and FADH2), thereby cutting off the supply of substrates to ETC at the upstream stage. Overall, this study demonstrates that triggering bimetallic ion-mediated metabolic disruptions induces an energy crisis in bacteria, providing a reference for multimodal antibacterial strategies.