Multifunctional carbon dots disrupt bacterial dormancy and reactivate macrophages to eliminate intracellular MRSA.

Intracellular methicillin-resistant Staphylococcus aureus (MRSA) persisting within macrophages induces immunoparalysis, leading to recurrent infections. This persistence primarily arises from its metabolic dormancy, which diminishes susceptibility to antimicrobials, and from its capacity to trigger oxidative stress-mediated macrophage damage. In this study, water-soluble folic acid carbon dots (FACDs) synthesized via hydrothermal carbonization and polycondensation chelate Cu and Co through surface functional groups to form stable bimetallic complexes, thereby yielding degradable nanodots capable of targeted and efficient inhibition of intracellular MRSA within macrophages. First, the pterin structure of the FACDs enables specific binding to folate receptors on macrophages, facilitating cellular internalization. Second, Cu disrupts the low-metabolic state of intracellular MRSA by interfering with amino acid and energy metabolism, inducing a cuproptosis-like bactericidal effect and clearing intracellular bacteria. Concurrently, Co alleviates oxidative stress-induced damage in macrophages, restoring and activating their phagocytic and bactericidal functions. Furthermore, real-time monitoring with a macrophage intracellular bacterial model in vitro and MRSA bioluminescence imaging in vivo demonstrated the dynamic antibacterial process of the CDs. Collectively, this study presents an innovative strategy whereby water-soluble bimetallic FACDs enable macrophage-targeted delivery, cuproptosis-like bactericidal activity, and immunological rescue, offering a comprehensive approach to eradicate intracellular MRSA.