Discriminating extracellular vesicles by their membranes

Extracellular Vesicles (EVs) are increasingly employed for targeted drug delivery and advanced diagnostic assays. However, the diagnostic application of EVs so far only relied on biochemical markers as in the case of prostate cancer. Pioneering work by Whitehead and by LeClaire showed that the diagnostic power of EVs can be significantly expanded by using the mechanical properties of EV membranes for mechanophenotyping. Inspired by this idea, we computationally characterised the mechanical properties of EVs released by the prostate cancer cell line PC-3 and their healthy counterparts, the prostasomes. Our work confirms that healthy and cancer EVs exhibit different mechanical properties. However, while Whitehead and LeClaire observed a softening of the membrane in cancer EVs, our analysis reveals that the membrane of PC-3 EVs is stiffer than that of healthy prostasomes. This suggests that the diagnostic interpretation of mechanical data will have to be done on a case-by-case basis. As experimental evidence suggests that EV membranes are asymmetric, we also explored the role of numerical and compositional asymmetry starting from the PC-3 composition. Our work shows that the tilt and splay moduli of the asymmetric PC-3 membrane are the average of the moduli of the corresponding symmetric membranes. This result confirms the predictions of the elastic theory of membranes, which have been recently challenged by experimental data. Finally, our work reveals coupling effects such that the moduli of a monolayer depend not only on its composition but also on the features of the companion leaflet.