Fig. 2

Overview of native extracellular RNA (exRNA) carriers. Unprotected RNAs are rapidly degraded in the extracellular space. Argonaute 2 (Ago2)-miRNA is found in circulation but its secretion mechanism is unknown, and it delivers via the receptor Neuropilin 1 (Nrp1). Apolipoprotein A-1 (ApoA1) is secreted by mainly the liver and intestine, and interacts with ABCA1, ABCG1, and SR-B1 in peripheral tissue to accumulate cholesterol and phospholipids. Discoidal nascent High Density Lipoprotein (HDL) is matured into spherical HDL through LCAT, PLTP, and CETP. Mature HDL is loaded with miRNA through an unknown mechanism. Nascent and mature HDL can interact with SR-B1 to deliver RNA and lipids, and lipid-free ApoA1 is released back into circulation. Spontaneous lipid transfers also play a large role in HDL function. EVs such as exosomes and microvesicles deliver RNA, as well as Ago2-miRNA and the retroviral Gag-like protein Arc. Arc has been found to mediate mRNA transport in the brain; non-exosomal Arc retains function but its prevalence is unknown. ABCA1, ATP-binding cassette subfamily A member 1; ABCG1, ATP-binding cassette subfamily G member 1; SR-B1, scavenger receptor class B type 1; LCAT, lecithin–cholesterol acyltransferase; CETP, cholesteryl ester transfer protein; PLTP, cholesteryl ester transfer protein; ARC, activity-regulated cytoskeleton-associated protein