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

Abstract

Methicillin-resistant <i>Staphylococcus aureus</i> (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 Zn²⁺ and vancomycin (Van) codelivered nanotherapeutic (named Man-Zn²⁺/Van NPs) was fabricated and characterized via mannose (Man) modification. Man-Zn²⁺/Van NPs exhibit significant inhibitory activity against extra- and intracellular MRSA and obviously decrease the minimum inhibitory concentration of Van. Man-Zn²⁺/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-Zn²⁺/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-Zn²⁺/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.