Argonautes in extracellular vesicles: artifact or selected cargo?

Argonaute-2 (Ago2) is a key component of the RNA-induced silencing complex that mediates downregulation of mRNA by miRNAs. Its presence in extracellular vesicles (EV) has been postulated to be important for the activity of EV-carried miRNA in modulating gene expression in recipient cells. However, whether it is in fact contained within EVs or is instead an extravesicular contaminant is controversial. In this opinion piece, we argue that the ability to detect Ago2 in EVs is a result of multiple factors, including cell source, cell signaling control of Ago2 trafficking to EVs, experimental conditions, and detection methods.