Unraveling the mechanisms that specify molecules for secretion in extracellular vesicles

Extracellular vesicles (EVs) are small membrane-bound organelles naturally released from cells and potentially function as vehicles of intercellular communication. Cells release numerous sub-species of EVs, including exosomes and microvesicles, which are formed via distinct cellular pathways and molecular machineries and contain specific proteins, RNAs and lipids. Accumulating evidence indicates that the repertoire of molecules packaged into EVs is shaped by both the physiological state of the cell and the EV biogenesis pathway involved. Although these observations intimate that precisely regulated pathways sort molecules into EVs, the underlying molecular mechanisms that direct molecules for secretion remain poorly defined. Recently, with the advancement of mass spectrometry, next-generation sequencing techniques and molecular biology tools, several mechanisms contributing to EV cargo selection are beginning to be unraveled. This review examines strategies employed to reveal how specific proteins, RNAs and lipids are directed for secretion via EVs.