Extracellular Vesicles (EVs), including Exosomes, are now recognized as vectors of intercellular communication capable of transferring nucleotides, lipids, and proteins from donor to acceptor cells. EV-mediated communication has been associated with many physiological and pathophysiological functions, including cancer, immune responses, cardiovascular diseases, lipid homeostasis, tissues regeneration and stem cell-based therapy.
EVs are being recognized as vectors of major importance for physiology in general, and appears as promising candidates for translational applications such as targeted therapeutics delivery.
However, the mechanisms responsible for EV delivery within the acceptor cells remain unknown at both the cellular and the molecular levels. How do vesicles enter cells? Is it receptor-dependent? How do vesicles deliver their contents within the cytosol of the acceptor cells? Does it require membrane fusion? If yes, what is the nature of the target membrane and the fusion machinery? Those basic questions are not yet answered.
This is not satisfying, especially considering how much we know about the cellular and molecular mechanisms that regulate the delivery of viruses or the transport of intracellular vesicles, which both share several physico-chemical properties with EVs.
It is therefore of high priority to close these gaps, especially when considering the high translational impact of EVs.
We developed cell-free and cell-based assays to accurately assess in a qualitative and quantitative manner the EV delivery process, especially the EV content release. Our results suggest that EV content delivery occurs within the endo-lysosomal compartment, through a process that is pH- and protein-dependent and that seems to involve membrane fusion. We are now aiming at identifying the core machinery that controls this process, to latter engineer EV-mimetics designed for targeted therapeutics delivery.