Bacterial infections are re-emerging as substantial threats to world well being because of the restricted number of antibiotics which might be able to overcoming antibiotic-resistant strains. By deterring such mutations while minimizing the necessity to develop new pathogen-specific antibiotics, immunotherapy gives a broad-spectrum therapeutic answer in opposition to bacterial infections. Particularly, pathology ensuing from extreme immune response (i.e. fibrosis, necrosis, exudation, breath obstacle) contributes considerably to adverse illness consequence. Herein, we current a nanoparticle that’s focused to activated macrophages and loaded with siRNA in opposition to the Irf5 gene. This formulation is ready to induce >80% gene silencing in activated macrophages in vivo, and it inhibits the extreme inflammatory response, producing a considerably improved therapeutic consequence in mouse fashions of bacterial an infection. The flexibility of the method is demonstrated utilizing mice with antibiotic-resistant Gram-positive (methicillin-resistant Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa) muscle and lung infections, respectively. Efficient depletion of the Irf5 gene in macrophages is discovered to considerably enhance the therapeutic consequence of contaminated mice, whatever the micro organism pressure and sort.