Rethinking Extracellular Vesicle Signaling.

Extracellular vesicles mediate intercellular communication through transport of bioactive cargo from producing to recipient cells. Cellular uptake and subsequent cytoplasmic release of internal cargo is often emphasized as the main mechanism of extracellular vesicle-mediated signaling. This article highlights two alternate modes of extracellular vesicle signaling based on surface binding without internalization: 'bind-and-stay', and 'bind-and-leave'. The transient binding of extracellular vesicles to multiple cells, inducing downstream signaling in each, challenges the conventional "one-vesicle-one-cell" model. We provide a forward-looking perspective on the efficiency and effectiveness of extracellular vesicle signaling modes and outline techniques that could be leveraged to study these interactions moving forward. An improved understanding of extracellular vesicle signaling is necessary for advancing fundamental biology and therapeutic development.