A disulfide molecule-vancomycin nanodrug delivery system efficiently eradicates intracellular bacteria.

Intracellular bacteria often lead to chronic and recurrent infections; however, most of the known antibiotics have poor efficacy against intracellular bacteria due to their poor cell membrane penetration efficiency into the cytosol. Here, a thiol-mediated nanodrug delivery system, named Van-DM NPs, was developed to improve vancomycin's penetration efficiency and intracellular antibacterial activities. Van-DM NPs were prepared through self-assembly of vancomycin (Van) and the disulfide molecule (DM) in NaOH buffer solution. On the one hand, the disulfide exchange reaction between Van-DM NPs and the bacterial surface enhances vancomycin accumulation in bacteria, increasing the local concentration of vancomycin. On the other hand, the disulfide exchange reaction between Van-DM NPs and the mammalian cell membrane triggered the translocation of Van-DM NPs across the mammalian cell membrane into the cell cytosol. These dual mechanisms promote antibacterial activities of vancomycin against both extracellular and intracellular bacteria S. aureus . Furthermore, in an intravenous S. aureus infection mouse model, Van-DM NPs exhibited high antibacterial capability and efficiently reduced the bacterial load in liver and spleen, where intracellular bacteria tend to reside. Altogether, the reported Van-DM NPs would be highly promising against intracellular pathogenic infections.