mGem: Guides or triggers? Extracellular RNAs beyond vesicular miRNAs

Despite a huge expansion in the last decades, several assumptions have directed, and perhaps pigeonholed, the evolution of the extracellular RNA (exRNA) field. For example, extracellular vesicles (EVs) have been assumed to be the main carriers of RNA molecules between cells. In parallel, microRNAs (miRNAs) have been assumed to be the main EV RNA cargo. However, from mammals to microbes, these assumptions do not seem to fall out of the data. In addition, miRNAs need to localize to the cytosol to be active but are likely to start in endosomes in most EV entry pathways. The mechanisms for their endosomal escape and the quantities of imported miRNAs required for their functions are not always considered. Without questioning the empirical evidence supporting EV-miRNA-mediated intercellular communication, we would like to shed light on the overlooked aspects of the exRNA biology that may bear important insights into how cells and organisms interact and sense one another.