Intracellular infection-responsive macrophage-targeted nanoparticles for synergistic antibiotic-immunotherapy of bacterial infection

Intracellular bacteria are considered one of the mechanisms that result in the failed therapy of bacterial infection and increase of antibiotic resistance. Nanotechnology-based drug delivery carriers have been receiving increasing attention for improving the intracellular antibacterial activity of antibiotics, but are accompanied by disadvantages such as complex preparation procedures, lack of active targeting, and monotherapy, which need to be further designed. Herein, the bacteria-infected macrophage targeted nanoparticle is fabricated to eliminate intracellular bacterial infections by antibiotic release, intracellular reactive oxygen species (ROS) level and proinflammatory response up-regulation. These nanoparticles were formed through the reaction of the amino group on selenocystamine dihydrochloride and the aldehyde group on oxidized dextran (ox-Dex), that encapsulate vancomycin (Van) through hydrophobic interaction. These nanoparticles could targeted uptake by macrophages via endocytosis, and response to the bacteria infected intracellular microenvironment (ROS and glutathione (GSH)) to controlled release antibiotic. Furthermore, the nanoparticles could consume intracellular GSH and promote a significant rise in level of ROS in macrophage, subsequently up-regulating proinflammatory response to reinforce antibacterial activity. These nanoparticles could accelerate bacteria-infected wound healing. This work fabricated a nanoparticle with bacteria-infected macrophage targeted and microenvironment-responsive antibiotic delivery, cellular ROS generation, and proinflammatory up-regulation activity to eliminate intracellular bacteria, which open up a new possibility for developing multifunctional drug delivery against intracellular infection.