Abstract
Extracellular vesicles (EVs) are 50–1000 nm vesicles secreted by virtually any cell type in the body. They are expected to transfer information from one cell or tissue to another in a short- or long-distance way. RNA-based transfer of information via EVs at long distances is an interesting well-worn hypothesis which is ~15 years old. We review from a quantitative point of view the different facets of this hypothesis, ranging from natural RNA loading in EVs, EV pharmacokinetic modeling, EV targeting, endosomal escape and RNA delivery efficiency. Despite the unique intracellular delivery properties endowed by EVs, we show that the transfer of RNA naturally present in EVs might be limited in a physiological context and discuss the lessons we can learn from this example to design efficient RNA-loaded engineered EVs for biotherapies. We also discuss other potential EV mediated information transfer mechanisms, among which are ligand–receptor mechanisms.
Highlights
Extracellular vesicles (EVs) are sub-cellular entities delineated by a lipid bilayer, containing biomolecules from parental cells, released either spontaneously or after induction
In terms of future improvement, achieving intra-vesicular loading of ∼10% of the EV cytosol, a similar fraction of what is achieved with lipid nanoparticle (LNP) would already be very interesting for EV based therapeutics as it would already represent ∼6000 siRNA per EV
Quantitative estimates from simplified pharmacokinetic and pharmacodynamic models based on quantitative data reported in the field suggest that information transfer through RNA by naturally circulating EVs may be limited in terms of efficacy at long distances
Summary
Extracellular vesicles (EVs) are sub-cellular entities delineated by a lipid bilayer, containing biomolecules from parental cells, released either spontaneously or after induction. Sverdlov published a critical opinion paper [14] questioning: (1) whether data on RNA transfer obtained in vitro in the literature are physiologically relevant in terms of molar concentration, and (2) whether the potential of exosomes and other EVs to deliver information (e.g., through nucleic acids, specific targeting or enhanced endosomal escape) is physiologically relevant. These issues are of critical importance when considering the design of EVs or the use of cell secretome vesicular fraction to deliver targeted RNA in a therapeutic purpose. We discuss in this context the data obtained in therapeutic settings with natural EVs and engineered EVs and compare it to RNA synthetic vectors like lipid nanoparticles
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
