The presence of RNAs in the extracellular milieu has sparked the hypothesis that RNA may play a role in mammalian cell–cell communication. As functional nucleic acids transfer from cell to cell in plants and nematodes, the idea that mammalian cells also transfer functional extracellular RNA (exRNA) is enticing. However, untangling the role of mammalian exRNAs poses considerable experimental challenges. This Review discusses the evidence for and against functional exRNAs in mammals and their proposed roles in health and disease, such as cancer and cardiovascular disease. We conclude with a discussion of the forward-looking prospects for studying the potential of mammalian exRNAs as mediators of cell–cell communication.
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The authors thank C. Hunter, J. Patton, S. Oberlin, H. Valadi, K. Vickers, M. Tewari, X. Breakfield, A. Krichevsky, M. Gruner, K. Weller and D. Knupp for their helpful feedback on the manuscript. This work was supported by grants to M.T.M.: U19CA179513, U01CA217882 and U42OD026647.
The authors declare no competing interests.
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“Extraordinary claims require extraordinary evidence.”
- Extracellular RNAs
(exRNAs). RNAs that are transcribed within a donor cell that are released into the extracellular space.
- Extracellular vesicles
Spheres of phospholipids and proteins secreted from the cell, including small and large extracellular vesicles, that contain various molecular cargoes such as RNA and proteins.
(RNP). A complex consisting of an RNA-binding protein that is bound to an RNA that is often recognized by an RNA-binding domain.
Particles of proteins and lipids that bind RNA, which are divided into different subtypes based on density, such as high-density lipoprotein and low-density lipoprotein.
- RNA interference
(RNAi). A process resulting in small RNAs binding to complementary RNA sequences to suppress their translation or direct their degradation.
(miRNAs). Small non-coding single-stranded RNAs that often regulate gene expression by binding to the 3′ untranslated region of mRNAs to induce translational repression, destabilization or cleavage of the transcript.
(RNases). Enzymes that cleave RNA, which are often found in the extracellular environment where they efficiently degrade RNAs that are not protected by other factors such as extracellular vesicles or proteins.
- Locked nucleic acids
Artifical nucleoside analogues that are more resistant to degradation than endogenous RNA.
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Gruner, H.N., McManus, M.T. Examining the evidence for extracellular RNA function in mammals. Nat Rev Genet (2021). https://doi.org/10.1038/s41576-021-00346-8