Functional macrophage-targeted nanoplatform for specific eradication of intracellular methicillin-resistant Staphylococcus aureus.

Drug-resistant infections caused by intracellular methicillin-resistant Staphylococcus aureus (MRSA) remain difficult to treat because conventional antibiotics exhibit limited accumulation and retention within infected macrophages. Here, we developed a macrophage-targeted, pH-responsive calcium carbonate nanoplatform (CaVPM) for intracellular delivery of vancomycin (Van). Porous CaCO₃ nanoparticles were used as the drug-loading core, polydopamine (PDA) provided a protective and functional shell, and a mannose-containing NBD ligand enabled macrophage targeting through mannose receptor recognition. The resulting CaVPM nanoparticles had a hydrodynamic diameter of approximately 255 nm and a Van drug-loading content of 5.1 ± 0.9% (w/w). CaVPM exhibited limited Van leakage under physiological conditions but accelerated drug release under acidic conditions. Mannose receptor-mediated uptake significantly enhanced intracellular delivery of CaVPM in RAW264.7 macrophages. Consistent with the enhanced cellular uptake, CaVPM increased intracellular Van accumulation from 28.52 ± 0.63 μg/mg protein for free Van to 57.58 ± 9.69 μg/mg and markedly reduced intracellular MRSA burden in vitro. In an MRSA peritonitis mouse model, intravenously administered CaVPM showed superior activity against intracellular bacteria compared with free Van. These findings demonstrate that mannose-directed cellular uptake combined with acid-responsive Van release can improve antibiotic delivery to intracellular MRSA reservoirs and provide a potential nanotherapeutic strategy for persistent intracellular infections.