Séminaire IBS : Cellular and Molecular Aspects of Extracellular Vesicle Uptake and Content Delivery

par Dr Gregory Lavieu (Université Paris Cité, INSERM U1316, CNRS UMR7057, Paris)

Extracellular Vesicles (EVs) 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, regeneration and stem cell-based therapy. The spectrum of tissues/cells that are capable of releasing or capturing EVs is broad and includes, neuronal cells, adipocytes, as well as immune cells.

EVs are therefore being recognized as vectors of major importance for physiology in general, and appears as promising candidates for translational applications such as targeted drug delivery. Using EVs or EV mimetics to deliver therapeutics (including the gene editing toolbox) to specific cells within the body would revolutionize cell/gene therapy.

However, the delivery process mechanisms within the acceptor cells remain unknown at both cellular and 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 as virus-free vectors for therapeutics delivery

I will present our recent efforts to assess EV uptake and content delivery in a qualitative and quantitative manner, and discuss the cellular and molecular mechanisms that are involved in this process. Then I will present our efforts to bioengineer EVs with enhanced properties to enable targeted therapeutics delivery.

References :

. Tognoli ML, Dancourt J, Bonsergent E, Palmulli R, de Jong OG, Van Niel G, Rubinstein E, Vader P, Lavieu G*. Lack of involvement of CD63 and CD9 tetraspanins in the extracellular vesicle content delivery process. Commun Biol. 2023.
. Bui S, Dancourt J, Lavieu G*. Virus Free-Method to Control EV-Cargo Loading and Delivery. ACS A Bio Mat. 2023.
. Dancourt J, Piovesana E, Lavieu G*. Efficient cell death mediated by bioengineered killer extracellular vesicles. Sci Rep. 2023.
. Bonsergent E, Grisard E, Buchrieser J, Schwartz O, Théry C, Lavieu G*. Quantitative characterization of extracellular vesicle uptake and content delivery within mammalian cells. Nat Commun. 2021
. Bonsergent, E. & Lavieu, G*. Content release of extracellular vesicles in a cell-free extract. FEBS Lett. 2019.

Hôte : Rémy Sadoul (IBS/Groupe Entrée et bourgeonnement des virus à enveloppe)