Metal Ion and Antibiotic Co-loaded Nanoparticles for Combating Methicillin-Resistant Staphylococcus aureus-Induced Osteomyelitis

Methicillin-resistant Staphylococcus aureus (MRSA) causes osteomyelitis (OM), which seriously threatens public health due to its antimicrobial resistance. To increase the sensitivity of antibiotics and eradicate intracellular bacteria, a Zn 2+ and vancomycin (Van) codelivered nanotherapeutic (named Man-Zn 2+ /Van NPs) was fabricated and characterized via mannose (Man) modification. Man-Zn 2+ /Van NPs exhibit significant inhibitory activity against extra- and intracellular MRSA and obviously decrease the minimum inhibitory concentration of Van. Man-Zn 2+ /Van NPs can be easily internalized by MRSA-infected macrophages and significantly accumulated in infected bone via Man-mediated targeting. In vivo experiments in a mouse OM model verified that Man-Zn 2+ /Van NPs significantly reduce the extra- and intracellular MRSA burden, improve gait patterns, increase bone mass, and decrease inflammatory cytokine expression. The antibacterial mechanism of Man-Zn 2+ /Van NPs includes destruction of the MRSA membrane, degeneration of intracellular proteins and DNA, inhibition of MRSA glycolysis, and intervention in the energy metabolism of bacteria. Overall, this metal–antibiotic nanotherapeutics strategy provides new insight for combating extra- and intracellular infections caused by MRSA-induced OM.