Fig. 1

Biogenesis pathways of main extracellular vesicles. The four primary types of extracellular vesicles, exosomes (40–100 nm), microvesicles (100–1000 nm), large oncosomes (1–10 μm), and apoptotic bodies (50–500 nm), are illustrated. The initiation step of exosome formation involves the creation of early endosomes, which happens subsequent to the endocytosis or uptake of extracellular fluids, particles, and viruses through receptor- and Clathrin-dependent or independent routes. Notably, if there are any plasma membrane receptors or membrane-integrated proteins located within the region of the endocytic membrane, their orientation changes from facing the outside of the cells to facing the endosomal lumen after endocytosis-mediated internalization. These receptors can then either be recycled to the plasma membrane or retained within the endosome. Exosomes are then formed through endosomal membrane inward budding to generate intraluminal vesicles (ILVs) via endosomal sorting complexes required for transport (ESCRT) complexes or an ESCRT-independent route through lipid rafts, such as the membrane-associated neutral sphingomyelinase (nSMase) and the ceramide-triggered pathway. As ILVs form, the orientation of plasma membrane receptors or membrane-integrated proteins within the endosome undergoes another change, transitioning from facing the endosomal lumen to facing the outside of the ILV. Both ESCRT-dependent and nSMase/ceramide-triggered exosomes can be inhibited by blockers such as Manumycin A, GW4869, and Altenusin. As ILVs accumulate within a single endosome during endosome maturation, the early endosome progresses into the late endosome, also referred to as the multivesicular bodies (MVBs). MVBs can proceed through two pathways: fusion with lysosomes for degradation, which involves the small GTPase Rab7, or secretion into the extracellular space as exosomes after MVB-plasma membrane fusion, a process regulated by small GTPases such as Rab11, Rab27 and Rab35. Microvesicles and large oncosomes are categorized as ectosomes, originating as outward buds from the plasma membrane. Apoptotic bodies result from the orderly fragmentation of apoptotic cells, and the formation of apoptotic bodies involves key roles played by caspase-3 substrates, including ROCK1, PANX1, and PLEXB2