Figure 1: EV Biogenesis and Interaction With Recipient Cells

Exosome formation starts with endocytosis, a process in which the cell membrane is pinched inward and captures bioactive molecules, resulting in the formation of the endosome. These molecules are sorted into smaller vesicles that bud from the perimeter membrane into the endosome lumen, forming vesicles; this leads to the multivesicular appearance of late endosomes and so they are also known as MVBs. From MSBs, exosome formation occurs by an ESCRT- and ceramide-dependent pathway. Cargo sorting into exosomes involves ESCRT and TSG101, ALIX, and Rab7a, and Rab27b. Exosomes are released into the extracellular space following the fusion of MVBs with the cell membrane, which is regulated by Rab27A, Rab11, and Rab31. Microvesicles are formed by the outward budding of the cell membrane, a process that is regulated by ARF6. Several routes of interaction between EVs and recipient cells have been described. First, EVs can directly activate target cell surface receptors. Second, EVs are able to transfer their biological content by membrane fusion with the recipient cell. Third, incorporation of EVs into target cells is mediated by endocytosis, pinocytosis, or phagocytosis. Using these interaction routes, EVs transfer their biological content containing nucleic acids such as mRNA, noncoding RNAs (microRNAs, long noncoding RNAs), proteins, cytokines, or bioactive lipids. mRNA = messenger RNA; MVB = multivesicular bodies.