Beyond the Bubble: A Debate on microRNA Sorting in Extracellular Vesicles.

Over the past decade, a scientific field has developed demonstrating microRNAs are actively sorted into extracellular vesicles via specific nucleotide motifs that interact with discrete RNA-binding proteins. These microRNAs are preferentially transported into recipient cells where they can regulate specific cellular pathways. This mechanism could have enormous potential in explaining how cells signal and regulate other cells nearby or at a distance. Tens of studies have built this theme of a regulated transport of microRNAs. However, some concerns exist about this field. Taken together, there are concerns of a lack of a consistent motif, RNA-binding protein, or preferential microRNA involved in this process. Here we provide expert and extensive analysis of the field that makes the cases for and against an active sorting mechanism. We provide potential explanations on why there is a lack of agreement. Most importantly, we provide ideas on how to move this field forward with more rigor and reproducibility. It is hoped that engaging in a scientific debate of the pros and cons of this field, more rigorous experiments can be performed to conclusively demonstrate this biological activity.