New insights into how small extracellular vesicles fuse with a model cellular membrane

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Extracellular vesicles (EVs) are nanosized cell-derived compartments with cargo functions. They can transport a wide range of molecules such as proteins, DNA, RNA, metabolites, and nutrients from cell to cell and throughout the body. EVs are an important player in several biological processes and, thanks to features like biocompatibility and small size, have a relevant therapeutic potential. These systems have been widely studied through the years, although various aspects of their physiology remain debated. Gaining insight into how EVs interact with cell membranes would substantially impact the biomedical sector.

Researchers from several European institutions, led by Dr. Valeria Rondelli from University of Milan,  Dr. Pietro Parisse from IOM- CNR and Dr. Loredana Casalis from Elettra Sincrotrone Trieste, employed various techniques to gain essential information on the fusion mechanism of small extracellular vesicles (sEVs) with a model plasma membrane. The employment of an artificial lipid bilayer allowed the investigation of different fusion mechanisms that are difficult to examine in a complex cellular environment.

Scheme of the experiment: Extracellular vesicles interaction with artificial model membranes in the form of small unilamellar vesicles and supported lipid bilayers is followed through AFM imaging in liquid, Neutron Reflectometry and Small Angle Neutron Scattering

This research work took advantage of a set of complementary techniques such as small-angle X-ray scattering (SAXS), small-angle neutron scattering (SANS) and neutron reflectometry (NR) to determine the interaction between sEVs and the model plasma membrane. SAXS is available at the Austrian CERIC Partner Facility at Elettra Sincrotrone Trieste, while neutron-based methods, SANS and NR, are available at the Hungarian CERIC Partner Facility at the Centre for Energy Research in Budapest.

Through this approach, the research group gave a molecular description of the interaction of small extracellular vesicles with a model plasma membrane, demonstrating that sEVs interact with the borders of specific domains of the membrane. Moreover, the biomolecules carried by the vesicle are diffused in a process different from the simple fusion. These results could lead to advancements in numerous biomedical sectors, including immune therapy, vaccination, regenerative medicine, and drug delivery.

ORIGINAL ARTICLE:

STRUCTURAL INSIGHTS INTO FUSION MECHANISMS OF SMALL EXTRACELLULAR VESICLES WITH MODEL PLASMA MEMBRANES, PERISSINOTTO F., RONDELLI V., SENIGAGLIESI B., BROCCA P., ALMÁSY L., BOTTYÁN L., MERKEL D.G., AMENITSCH H., SARTORI B., PACHLER K., MAYR M., GIMONA M., ROHDE E., CASALIS L. & PARISSE P., (2021), NANOSCALE, 13(10), 5224-5233