The study reports the development of polymeric nanoparticles (PNPs) enclosed in the plasma membrane of human platelets, which are a unique population of cellular fragments that adhere to disease-relevant substrates. The resulting PNPs possess a right-side-out unilamellar membrane coating functionalized with immunomodulatory and adhesion antigens associated with platelets. Compared to uncoated particles, the platelet membrane-cloaked PNPs show reduced cellular uptake by macrophage-like cells and are absent of particle-induced complement activation. The PNPs exhibit platelet-mimicking properties such as selective adhesion to damaged human and rodent vasculatures and enhanced binding to platelet-adhering pathogens. In experimental rat models of coronary restenosis and a mouse model of systemic bacterial infection, docetaxel and vancomycin, respectively, show enhanced therapeutic efficacy when delivered by the platelet-mimetic PNPs. The multifaceted biointerfacing enabled by the platelet membrane cloaking method provides a new approach for developing functional nanoparticles for disease-targeted delivery.The study reports the development of polymeric nanoparticles (PNPs) enclosed in the plasma membrane of human platelets, which are a unique population of cellular fragments that adhere to disease-relevant substrates. The resulting PNPs possess a right-side-out unilamellar membrane coating functionalized with immunomodulatory and adhesion antigens associated with platelets. Compared to uncoated particles, the platelet membrane-cloaked PNPs show reduced cellular uptake by macrophage-like cells and are absent of particle-induced complement activation. The PNPs exhibit platelet-mimicking properties such as selective adhesion to damaged human and rodent vasculatures and enhanced binding to platelet-adhering pathogens. In experimental rat models of coronary restenosis and a mouse model of systemic bacterial infection, docetaxel and vancomycin, respectively, show enhanced therapeutic efficacy when delivered by the platelet-mimetic PNPs. The multifaceted biointerfacing enabled by the platelet membrane cloaking method provides a new approach for developing functional nanoparticles for disease-targeted delivery.