is a leading human pathogen capable of producing severe invasive infections such as bacteremia, sepsis and endocarditis with high morbidity and mortality, exacerbated by expanding antibiotic-resistance exemplified by methicillin-resistant strains (MRSA). pathogenesis is fueled by secretion of secreted toxins including the membrane damaging pore-forming α-toxin that have diverse cellular targets including epithelium, endothelium, leukocytes and platelets. Here we examine human platelet membrane-coated nanoparticles (PNPs) as a biomimetic decoy strategy to neutralize toxins and preserve host cell defense functions. PNPs blocked platelet damage induced by secreted toxins, supporting platelet activation and bactericidal activity. Likewise, PNPs blocked macrophage damage induced by secreted toxins, supporting macrophage oxidative burst and nitric oxide production and bactericidal activity, and diminishing MRSA-induced neutrophil extracellular trap release. In a mouse model of MRSA systemic infection, PNP administration reduced bacterial counts in the blood and protected against mortality. Taken together, the present work provides proof-of-principle of therapeutic benefit of PNPs in toxin neutralization, cytoprotection and increased host resistance to invasive infection.