A novel method for nanoparticle biointerfacing is described, where polymeric nanoparticles are enclosed in the plasma membrane of human platelets, creating platelet membrane-cloaked nanoparticles (PNPs). These PNPs mimic platelet properties, including immunocompatibility, adhesion to damaged vasculature, and binding to pathogens. Compared to uncoated particles, PNPs show reduced uptake by macrophage-like cells and no complement activation. PNPs exhibit platelet-mimicking behaviors such as selective adhesion to damaged vasculature and enhanced binding to pathogens. In experimental models, docetaxel and vancomycin delivered by PNPs showed enhanced therapeutic efficacy. The platelet membrane cloaking method enables multifaceted biointerfacing, offering a new approach for disease-targeted delivery. PNPs were prepared by fusing human platelet membrane with 100 nm PLGA nanoparticles. Physicochemical characterization showed PNPs were larger and had equivalent surface charge to platelets. PNPs retained and enriched membrane proteins, including immunomodulatory and adhesion antigens. PNPs showed enhanced collagen adhesion and reduced complement activation. In a rat model of coronary restenosis, PNP-Dtxl inhibited neointima growth. In a mouse model of systemic bacterial infection, PNP-Vanc showed improved antimicrobial efficacy. The study validates the feasibility of using biomembrane interfaces to improve infectious disease treatment. PNPs have potential applications in cardiovascular diseases, traumas, cancers, and acute inflammations. The platform benefits from existing transfusion medicine and nanotherapeutic infrastructures. PNPs showed good stability and storage properties. The study provides a promising approach for targeted drug delivery and disease treatment.A novel method for nanoparticle biointerfacing is described, where polymeric nanoparticles are enclosed in the plasma membrane of human platelets, creating platelet membrane-cloaked nanoparticles (PNPs). These PNPs mimic platelet properties, including immunocompatibility, adhesion to damaged vasculature, and binding to pathogens. Compared to uncoated particles, PNPs show reduced uptake by macrophage-like cells and no complement activation. PNPs exhibit platelet-mimicking behaviors such as selective adhesion to damaged vasculature and enhanced binding to pathogens. In experimental models, docetaxel and vancomycin delivered by PNPs showed enhanced therapeutic efficacy. The platelet membrane cloaking method enables multifaceted biointerfacing, offering a new approach for disease-targeted delivery. PNPs were prepared by fusing human platelet membrane with 100 nm PLGA nanoparticles. Physicochemical characterization showed PNPs were larger and had equivalent surface charge to platelets. PNPs retained and enriched membrane proteins, including immunomodulatory and adhesion antigens. PNPs showed enhanced collagen adhesion and reduced complement activation. In a rat model of coronary restenosis, PNP-Dtxl inhibited neointima growth. In a mouse model of systemic bacterial infection, PNP-Vanc showed improved antimicrobial efficacy. The study validates the feasibility of using biomembrane interfaces to improve infectious disease treatment. PNPs have potential applications in cardiovascular diseases, traumas, cancers, and acute inflammations. The platform benefits from existing transfusion medicine and nanotherapeutic infrastructures. PNPs showed good stability and storage properties. The study provides a promising approach for targeted drug delivery and disease treatment.