Matrix mechanics and water permeation regulate extracellular vesicle transport

Cells release extracellular vesicles (EVs) to communicate over long distances, requiring EVs to traverse the extracellular matrix (ECM). However, given that the size of EVs is usually larger than the mesh size of the ECM, it is not clear how they can travel through the dense ECM. Here we show that in contrast to synthetic nanoparticles, EVs readily transport through nanoporous ECM. Using engineered hydrogels, we demonstrate that the mechanical properties of the matrix regulate anomalous EV transport under confinement. Matrix stress relaxation allows EVs to overcome confinement, and a higher crosslinking density facilitates fluctuating transport motion through the polymer mesh, leading to free diffusion and fast transport. Furthermore, water permeation through aquaporin-1 mediates EV deformability, which further supports EV transport in hydrogels and decellularized matrix. Our results provide evidence of the nature of EV transport within confined environments and demonstrate an unexpected dependence on matrix mechanics and water permeation.