FIGURE 1.

The biogenesis and composition of exosomes. Exosomes originate as endocytic vesicles through invagination of the cell membrane, which results in the formation of early exosomes and, subsequently, late exosome called MVBs. MVBs contain ILV which are formed from budding of the endosomal membrane and are called exosomes. When MVBs fuse with the plasma membrane, they give rise to the release of exosomes into the extracellular space. (A) Endosomal proteins such as CD9, Alix, and TSG101 may be incorporated into exosomes during their assembly to facilitate this process. (B) AGO2 and GW182 are two important components of the RNA-induced silencing complex (RISC), which associate with MVBs so as to mediate miRNA sorting into exosomes. (C) Subsequent fusion of cell-derived exosomes with the plasma membrane through their CD9 (tetraspanin) interaction with surface glycoproteins on target cells gives rise to cytosolic delivery of the siRNA directly. This process is involved in the creation of temporary RNAi. (D) Exosomes originate from inward budding in the lumen of the MVB through which the cytoplasmic content from the cell of origin and also viral components, including mRNA and small non-coding RNA and viral glycoproteins are incorporated into the exosome, and then released as a selective cargo in viral-infected cells. These virus-modified exosomes display the original surface markers and cell membrane as the parent cells. (E) Bioengineered or virus-modified exosomes are designed to express a selective set of proteins and small, non-coding RNAs to target specific receptors. Exosomes then fuse with the endosomal membrane to release their non-coding RNAs into the cytoplasm so as to load siRNA into the RNAi (RISC) complex of the target cells in order to prevent mRNA translation into protein. Acronyms: RISC, RNA-induced silencing complex; RNAi, RNA interference; siRNA, small interference RNA; MVBs, multivesicular bodies.