© 2018 by the authors.We report on the interaction of small (> 150 nm) extracellular vesicles (EVs) with silicon surface. The study is conducted by leveraging Si nanomechanical microcantilever sensors actuated in static and dynamic modes, that allow tracking of EV collective adsorption energy and adsorbed mass. Upon incubation for 30 min at about 10 nM concentration, EVs isolated from human vascular endothelial cell (HVEC) lines form a patchy layer that partially covers the Si total surface. Formation of this layer releases a surface energy equal to (8 ± 1) mJ/m2, typical of weak electrostatic interactions. These findings give a first insight into the EV-Si interface and proof the possibility to realize new hybrid biointerphases that can be exploited as advanced models to investigate properties of biological membranes and/or biosensing platforms that take advantage of biomolecules embedded/supported in membranes.