Membranes on the move: The functional role of the extracellular vesicle membrane for contact-dependent cellular signalling.

Extracellular vesicles (EVs), lipid-enclosed structures released by virtually all life forms, have gained significant attention due to their role in intercellular and interorganismal communication. Despite their recognized importance in disease processes and therapeutic applications, fundamental questions about their primary function remain. Here, we propose a different perspective on the primary function of EVs, arguing that they serve as essential elements providing membrane area for long-distance, contact-dependent cellular communication based on protein-protein interaction. While EVs have been recognized as carriers of genetic information, additional unique advantages that they could provide for cellular communication remain unclear. Here, we introduce the concept that the substantial membrane area provided by EVs allows for membrane contact-dependent interactions that could be central to their function. This membrane area enables the lateral diffusion and sorting of membrane ligands like proteins, polysaccharides or lipids in two dimensions, promoting avidity-driven effects and assembly of co-stimulatory architectures at the EV-cell interface. The concept of vesicle-induced receptor sequestration (VIRS), for example, describes how EVs confine and focus receptors at the EV contact site, promoting a dense local concentration of receptors into signalosomes. This process can increase the signalling strength of EV-presented ligands by 10-1000-fold compared to their soluble counterparts. The speculations in this perspective advance our understanding of EV-biology and have critical implications for EV-based applications and therapeutics. We suggest a shift in perspective from viewing EVs merely as transporters of relevant nucleic acids and proteins to considering their unique biophysical properties as presentation platforms for long-distance, contact-dependent signalling. We therefore highlight the functional role of the EV membrane rather than their content. We further discuss how this signalling mechanism might be exploited by virus-transformed or cancer cells to enhance immune-evasive mechanisms.