Vitamin C–functionalized copper nanozymes for treating drug-resistant intracellular infections and hyperinflammation

Bacterial infections, particularly drug-resistant intracellular infections, remain a major clinical challenge due to antibiotic resistance and immune evasion. Here, we report a vitamin C-functionalized copper-based nanozymes (CVs) as multifunctional therapeutic agents capable of simultaneously eradicating intracellular bacteria and mitigating hyperinflammation. Benefiting from excellent biocompatibility and acid-responsive activity, CVs exhibit potent bactericidal, reactive oxygen species (ROS)-scavenging, and immunomodulatory functions. Mechanistically, CVs enter bacterial cytoplasm <i>via</i> copper transporters, induce intracellular copper overload, disrupt the tricarboxylic acid cycle, and promote lipid peroxides accumulation, thereby triggering a cuproptosis-like bacterial death pathway. Moreover, CVs mimic superoxide dismutase activity to efficiently eliminate excessive ROS, and regulate immune responses by suppressing macrophage polarization toward the pro-inflammatory M1 phenotype while reducing pro-inflammatory cytokine production. These combined effects attenuate inflammation and promote tissue repair within infection-associated microenvironments. In a methicillin-resistant <i>Staphylococcus aureus</i> (MRSA)-induced peritonitis mouse model, CVs achieved robust intracellular bacterial clearance and inflammation resolution, underscoring their potential as next-generation copper-based nanomaterials for treating refractory intracellular bacterial infections and hyperinflammation-related disorders.