Atherosclerosis is the leading cause of mortality globally. RBC-platelet hybrid membrane-coated nanoparticles ([RBC-P]NPs), which biologically mimic platelets in vivo, display evidence of anti-atherosclerotic activity. The efficacy of a targeted RBC-platelet hybrid membrane-coated nanoparticles ([RBC-P]NP)-based approach was investigated as a primary preventive measure against atherosclerosis. A ligand-receptor interactome analysis conducted with circulating platelets and monocytes derived from CAD patients and healthy controls identified CXCL8-CXCR2 as a key platelet ligand-monocyte receptor dyad in CAD patients. Based on this analysis, a novel anti-CXCR2 [RBC-P]NP that specifically binds to CXCR2 and blocks the interaction between CXCL8 and CXCR2 was engineered and characterized. Administering anti-CXCR2 [RBC-P]NPs to Western diet-fed Ldlr(-/-) mice led to diminished plaque size, necrosis, and intraplaque macrophage accumulation relative to control [RBC-P]NPs or vehicle. Importantly, anti-CXCR2 [RBC-P]NPs demonstrated no adverse bleeding/hemorrhagic effects. A series of in vitro experiments was conducted to characterize anti-CXCR2 [RBC-P]NP's mechanism of action in plaque macrophages. Mechanistically, anti-CXCR2 [RBC-P]NPs inhibited p38 alpha (Mapk14)-mediated, pro-inflammatory M1 skewing and corrected efferocytosis in plaque macrophages. This targeted [RBC-P]NP-based approach, in which the cardioprotective effects of anti-CXCR2 [RBC-P]NP therapy overweighs its bleeding/hemorrhagic risks, could potentially be used to proactively manage atherosclerotic progression in at-risk populations.