Activated platelet membrane vesicles for broad-spectrum bacterial pulmonary infections management

Abstract

The development of new antibiotics has lagged behind the rapid evolution of bacterial resistance, prompting the exploration of alternative antimicrobial strategies. Host-directed therapy (HDT) has emerged as a promising approach by harnessing innate immune system's natural defense mechanisms, which reduces reliance on antibiotics, and mitigates the development of resistance. Building on the important role of platelets in host immunity, activated platelet membrane vesicles (PLTv) are developed here as a host-directed therapy for broad-spectrum antibacterial infection management, leveraging several key mechanisms of action. PLTv neutralizes bacterial toxins, thereby reducing cytotoxicity. The presence of platelet receptors on PLTv enables them to act as decoys, binding bacteria through receptor interactions and facilitating their phagocytosis by neutrophils and macrophages. Additionally, PLTv bound to bacteria promote the formation of neutrophil extracellular traps (NETs), enhancing the immune system's ability to trap and kill bacteria. In mouse models of pulmonary infections caused by the Methicillin-resistant Staphylococcus aureus, P. aeruginosa, and A. baumannii, administration of PLTv significantly reduces bacterial counts in the lungs and protects against mortality. Taken together, the present work highlights PLTv as a promising host-directed therapy for combating broad-spectrum pulmonary drug-resistant bacterial infections, leveraging their ability to neutralize toxins, act as decoys, promote phagocytosis, and facilitate NETs formation.