Uncontrolled inflammation, featuring the aggravated mobilization of Ly6Chigh inflammatory monocytes (Mos), may cause high morbidity and mortality in the pathogenesis of sepsis-associated immune disorders. Inspired by the similar membrane protein profile of extracellular vehicles (EVs) and their parent cells, EVs are generated from immortalized bone marrow-derived macrophages (Mps) for Mo/Mp-targeting drug delivery. Compared with MSC-EVs, Mac-EVs are more efficiently internalized by inflammatory Mo/Mps in vitro as well as by septic spleen in vivo. By loading with siRNA targeting the chemokine receptor CCR2, the mediator for chemotaxis of inflammatory Mo/Mps, Mac-EVsiCCR2 not only restrains chemotaxis of inflammatory Mo/Mps but also relieves septic symptoms in mice by limiting the mobilization of splenic inflammatory monocytes and calming the subsequent serum cytokine storm. The current study provides functional evidence for the successful therapeutic targeting of septic inflammatory Mos, mandating the clinical development of CCR2 inhibition in patients with infectious diseases.