How do extracellular vesicles deliver their content into target cells

Extracellular vesicles (EVs) are secreted all cells and act as mediators of intercellular communication, carrying different components such as proteins, RNA and DNA. Despite many studies have highlighted the effects of EV cargo on target recipient cells, how these vesicles release their content within the cell is still an open question. Inspired by decades of research in virology we tested whether tumor-derived EVs released from ovarian cancer cells can fuse with target membranes in ‘a viral-like escape mechanism’, and whether this process is protein-mediated. Using an in vitro FRET biophysical essays with lipid model membranes, we show that extracellular vesicles are indeed able to perform fusion, and more importantly that the fusion process is pH triggered. Additionally, our results clearly demonstrate that the process depends on the biophysical properties of the target membrane, much like viral fusion. We complement the in vitro experiments with cryo-TEM and cryo-CLEM imaging to visualize the fusion process. Ultimately our research aims at identifying the fusogens (i.e. proteins) responsible for this mechanism, which would open up to potential therapeutic and drug-delivery platforms.