Extracellular vesicle biogenesis and release machinery (EV biogenesis/release machinery)

The extracellular vesicle (EV) biogenesis and release machinery is a sophisticated multi-protein system responsible for the formation, cargo selection, and secretion of membrane-bound vesicles, such as exosomes and microvesicles, into the extracellular environment [10, 15]. This machinery encompasses several distinct pathways, most notably the Endosomal Sorting Complex Required for Transport (ESCRT) pathway, which drives the formation of intraluminal vesicles within multivesicular bodies (MVBs), and the ESCRT-independent pathway mediated by neutral sphingomyelinase 2 (nSMase2) and ceramide [1, 13]. Small GTPases of the Rab family, such as Rab27a and Rab27b, are critical for the transport of MVBs to the plasma membrane and their subsequent fusion to release exosomes [1, 16]. In various diseases, particularly cancer and neurodegeneration, this machinery is dysregulated or hijacked to facilitate the spread of oncogenic signals, misfolded proteins (e.g., tau, alpha-synuclein), and pro-inflammatory factors [5, 15, 18]. Pharmacological inhibition of this machinery using agents like GW4869 (targeting nSMase2) or Manumycin A (targeting Ras/Rab signaling) is being explored as a strategy to disrupt pathological intercellular communication and enhance the efficacy of existing therapies [2, 12, 21]. However, the essential role of EV-mediated communication in normal physiology presents significant challenges for achieving therapeutic selectivity and minimizing off-target effects [5, 13].

Other names

Exosome biogenesis pathwayMicrovesicle shedding machineryEV secretion pathwayEndosomal sorting complex required for transport (ESCRT) machinerynSMase2-ceramide pathway

Inhibition of neutral sphingomyelinase 2 (nSMase2) to prevent ceramide-mediated membrane budding [12, 15]; inhibition of farnesyltransferase to disrupt Ras/Rab-mediated vesicle trafficking [1, 2]; inhibition of calpains and ROCK to prevent microvesicle shedding from the plasma membrane [1, 9]; and disruption of the ESCRT complex to prevent intraluminal vesicle formation [1, 15].