Background <p>Platelets play a critical role in the pathophysiology of acute lung injury (ALI) by activating neutrophils and promoting the formation of neutrophil extracellular traps (NETs). Excessive NETs formation exacerbates lung injury by triggering inflammation, impairing essential alveolar macrophage functions and activating the coagulation cascade. Consequently, inhibiting NETs formation represents a promising strategy for treating ALI.</p> Methods <p>In this study, we developed platelet membrane-coated nanoparticles (PNPs) by encapsulating poly(lactic-co-glycolic acid, PLGA)‌ nanoparticles within platelet membranes, and we characterized their physicochemical and functional properties. We investigated the effects of PNPs on platelet activation, NETs formation, mitochondrial ROS (mtROS) production and Syk phosphorylation in vitro. Furthermore, we evaluated the therapeutic effects of PNPs on acute lung inflammatory responses in a murine model.</p> Results <p>Compared with red blood cell membrane-coated nanoparticles (RBC-NPs), PNPs significantly inhibited both platelet activation and NETs formation. Mechanistic studies demonstrated that NETs generation was markedly attenuated via CD62P signaling inhibition in platelets and mitochondrial ROS scavenging in neutrophils (using mito-TEMPO), and these treatments exhibited a suppression efficiency that was comparable to that of PNPs treatment. In vivo experiments revealed that PNPs preferentially accumulated in the lungs of mice with ALI, reducing neutrophil infiltration and NETs formation. Furthermore, PNP treatment attenuated lung injury, as evidenced by reduced collagen deposition, decreased total protein levels and cell numbers in BALF, and decreased levels of proinflammatory cytokines in the lungs.</p> Conclusions <p>Our findings demonstrate that PNPs have potential for use in treating ALI by simultaneously attenuating platelet activation and NETs formation.</p>