Figure 1.

Biology of EV ncRNAs

(A) The biogenesis of ncRNAs and EVs. miRNA genes are transcribed into pri-miRNAs by RNA polymerase II (Pol II), and further cleaved by Drosha and DGCR8 to generate pre-miRNAs. After exporting into cytoplasm, pre-miRNAs are cleaved by Dicer to produce a miRNA duplex. Then the miRNA duplex loads on AGO. One strand of the duplex is selectively anchored into the AGO to form the RISC complex, thereby regulating the expression of target mRNA. circRNAs get their closed loop structures through back-splicing in nucleus. circRNAs are composed of extrons and/or introns depending on the methods of lariat-driven circularization, intron-pairing-driven circularization, and intron cyclization. lncRNA genes are transcribed through the mediation of Pol I/II to form lnc-pri-miRNAs, and are processed by RNase P/H to generate mature lncRNAs and pre-miRNAs. Mature ncRNAs are then sorted into MVBs. The MVBs are finally released as EVs in a Rab27b-dependent manner, or transported into lysosomes for degradation. (B) EVs can be internalized by recipient cells in different ways, such as phagocytosis, membrane fusion, clathrin-dependent endocytosis, caveolae-mediated endocytosis, and micropinocytosis. Once entering the recipient cells, EV ncRNAs exert their biological functions by acting as miRNA sponges, protein baits, protein scaffolds, and encoding proteins.