Intracellular bacteria are considered to play a key role in the failure of bacterial infection therapy 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, necessitating further design improvements. Herein, nanoparticles targeting bacteria-infected macrophages are fabricated to eliminate intracellular bacterial infections via antibiotic release and upregulation of intracellular reactive oxygen species (ROS) levels and proinflammatory responses. These nanoparticles were formed through the reaction of the amino group on selenocystamine dihydrochloride and the aldehyde group on oxidized dextran (ox-Dex), which encapsulates vancomycin (Van) through hydrophobic interactions. These nanoparticles could undergo targeted uptake by macrophages via endocytosis and respond to the bacteria-infected intracellular microenvironment (ROS and glutathione (GSH)) for controlled release of antibiotics. Furthermore, these nanoparticles could consume intracellular GSH and promote a significant increase in the level of ROS in macrophages, subsequently up-regulating the proinflammatory response to reinforce antibacterial activity. These nanoparticles can accelerate bacteria-infected wound healing. In this work, nanoparticles were fabricated for bacteria-infected macrophage-targeted and microenvironment-responsive antibiotic delivery, cellular ROS generation, and proinflammatory up-regulation activity to eliminate intracellular bacteria, which opens up a new possibility for multifunctional drug delivery against intracellular infection.