Staphylococcus (S.) aureus is a leading human pathogen capable of producing severe invasive infections 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. aureus pathogenesis is fueled by the secretion of toxins—such as the membrane-damaging pore-forming atoxin,
which have diverse cellular targets including the epithelium, endothelium, leukocytes, and platelets. 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 bactericidal
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 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 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.