Staphylococcus aureus (S.aureus) is a leading human pathogen capable of producing severe invasive infec-tions such as bacteremia,sepsis,and endocarditis with high morbidity and mortality,exacerbated by the increasingly widespread antibiotic resistance exemplified by methicillin-resistant strains (MRSA).S.aur-eus pathogenesis is fueled by the secretion of toxins-such as the membrane-damaging pore-forming α-toxin,which have diverse cellular targets including the epithelium,endothelium,leukocytes,and plate-lets.Here,we examine the use of human platelet membrane-coated nanoparticles (PNPs) as a biomimetic decoy strategy to neutralize S.aureus toxins and preserve host cell defense functions.The PNPs blocked platelet damage induced by S.aureus secreted toxins,thereby supporting platelet activation and bacteri-cidal activity.Likewise,the PNPs blocked macrophage damage induced by S.aureus secreted toxins,thus supporting macrophage oxidative burst,nitric oxide production,and bactericidal activity,and diminish-ing 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 results from the present work provide a proof of principle of the therapeutic benefit of PNPs in toxin neutralization,cytoprotection,and increased host resistance to invasive S.aureus infection.