Entry and exit of extracellular vesicles to and from the blood circulation

Extracellular vesicles (EVs) are biological nanoparticles that promote intercellular communication by delivering bioactive cargo over short and long distances. Short-distance communication takes place in the interstitium, whereas long-distance communication is thought to require transport through the blood circulation to reach distal sites. Extracellular vesicle therapeutics are frequently injected systemically, and diagnostic approaches often rely on the detection of organ-derived EVs in the blood. However, the mechanisms by which EVs enter and exit the circulation are poorly understood. Here, the lymphatic system and transport across the endothelial barrier through paracellular and transcellular routes are discussed as potential pathways for EV entry to and exit from the blood circulatory system. This Perspective discusses the current understanding of extracellular vesicles within the context of their movement into and out of blood circulation, with an outlook on leveraging extracellular vesicle nanobiology for mechanistic insights as well as diagnostic and nanotherapeutic applications in both physiological and pathological contexts.