Chiral Single‐Atom Nanozymes‐Enabled ROS Catalysis and Metal Transport Regulation Cooperatively Induce Ferroptosis to Treat Bacterial Infections

ABSTRACT Nanozyme‐driven ferroptosis provides a promising therapeutic strategy against drug‐resistant bacterial infections by inducing iron overload and oxidative stress. However, bacterial metal transport proteins (MTP) and antioxidant systems can reduce iron accumulation and lipid peroxidation, limiting the efficacy of ferroptosis‐based therapies and promoting resistance. Single‐atom and chiral nanozymes, with their high atomic utilization and catalytic specificity, may provide an effective approach to overcoming bacterial defense mechanisms, which has been not exploited. In this study, we report D‐chiral single‐atom iron–carbon dot nanozymes (DFe‐NSC) for effective bacterial infection treatment. Compared to L‐chiral form (LFe‐NSC), DFe‐NSC exhibits significantly higher peroxidase (POD)‐like and glutathione peroxidase (GPx)‐like activities. The enhanced catalytic activity promotes reactive oxygen species (ROS) generation and glutathione depletion, disrupting bacterial redox homeostasis. More intriguingly, DFe‐NSC more effectively modulates the expression and iron‐regulatory function of MTP (including Fur and FtnA) than LFe‐NSC. This will induce substantial accumulation of Fe 2 ⁺ intracellularly and thereafter lipid peroxidation, thereby facilitating the bactericidal effects of ferroptosis‐like cell death. Resultantly, DFe‐NSC exhibit markedly enhanced antibacterial and antibiofilm activities in diabetic infected wound and osteomyelitis models. This study introduces a chiral catalysis–MTP regulation strategy to induce bacterial ferroptosis‐like death, providing a promising alternative for drug‐resistant infection treatment.