Quaternary Ammonium Chitosan-functionalized Mesoporous Silica Nanoparticles: A Promising Targeted Drug Delivery System for the Treatment of Intracellular MRSA Infection

The limited membrane permeability and bacterial resistance pose significant challenges in the management of intracellular drug-resistant bacterial infections. To overcome this issue, we developed a bacterial-targeted drug delivery system based on quaternary ammonium chitosan-modified mesoporous silica nanoparticles (MSN-NH-CFP@HACC) for the treatment of intracellular Methicillin-resistant Staphylococcus aureus (MRSA) infections. This system utilizes amino-functionalized mesoporous silica nanoparticles to efficiently load cefoperazone (CFP), and the nanoparticles' surface is coated with 2-hydroxypropyltrimethyl ammonium chloride chitosan (HACC) to target bacteria and enhance macrophage uptake. The findings indicate that MSN-NH-CFP@HACC nanoparticles are efficiently internalized by macrophages, demonstrate accelerated drug release in acidic environments, and exhibit enhanced antibacterial properties, effectively suppressing the proliferation and intracellular escape of MRSA. Moreover, HACC enhances the bacterial capture ability of the nanoparticles and reduces resistance by disrupting bacterial membrane structures and inhibiting bacterial β-lactamase activity. In a murine model of MRSA bacteremia, MSN-NH-CFP@HACC exhibited remarkable antibacterial efficacy and significantly attenuated severe inflammatory responses. In conclusion, MSN-NH-CFP@HACC represent a promising antibiotic delivery system with exceptional antibacterial efficacy and favorable biocompatibility, thus presenting a novel strategy for addressing intracellular drug-resistant bacterial infections and demonstrating significant potential for clinical application.