Cells release extracellular vesicles (EVs) to communicate over long distances, which requires 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 the confinement, and a higher crosslinking density facilitates a fluctuating transport motion through the polymer mesh, which leads to free diffusion and fast transport. Furthermore, water permeation through aquaporin-1 mediates the EV deformability, which further supports EV transport in hydrogels and a decellularized matrix. Our results provide evidence for the nature of EV transport within confined environments and demonstrate an unexpected dependence on matrix mechanics and water permeation.
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The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.
The codes used to analyse the data in this study are available from the corresponding author upon reasonable request.
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We thank B. Hoffman (Duke University) and L. Cai (University of Virginia) for critical reading of the manuscript and invaluable comments. We acknowledge P. Toth and the Core Imaging Facility at UIC, J. Li at the Department of Pharmacology at UIC, T. Foroozan at the UIC Nanotechnology Core Facility, T. Teng and J. Lee at the Department of Bioengineering at UIC, A. Song at UIC and the ANTEC facility at Northwestern University for their technical help and support. This work made use of instruments in the Fluorescence Imaging Core (Research Resources Center, UIC). This work was supported by National Institutes of Health Grant R01-HL141255 (J.-W.S.), R00-HL125884 (J.-W.S.), T32 HL07829 (S.L.) and American Heart Association Grant 19PRE34380087 (S.L.).
The authors declare no competing interests.
Peer review information Nature Nanotechnology thanks Gregor Fuhrmann, Neill Turner and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Supplementary Figs. 1–9, Table 1 and captions for Supplementary Videos 1–6.
Tracking data overlaid with imaging data for representative transport of a single EV in stiff stress relaxing matrix shown in Fig. 3A. The length scale is micrometers and the time scale is seconds.
Tracking data overlaid with imaging data for representative transport of a single EV in soft stress relaxing matrix shown in Fig. 3A. The length scale is micrometers and the time scale is seconds.
Tracking data overlaid with imaging data for representative transport of a single EV in stiff elastic matrix shown in Fig. 3A. The length scale is micrometers and the time scale is seconds.
Tracking data overlaid with imaging data for representative transport of multiple EVs in stiff stress relaxing matrix. The length scale is micrometers and the time scale is seconds.
Tracking data overlaid with imaging data for representative transport of multiple EVs in soft stress relaxing matrix. The length scale is micrometers and the time scale is seconds.
Tracking data overlaid with imaging data for representative transport of multiple EVs in stiff elastic matrix. The length scale is micrometers and the time scale is seconds.
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Lenzini, S., Bargi, R., Chung, G. et al. Matrix mechanics and water permeation regulate extracellular vesicle transport. Nat. Nanotechnol. 15, 217–223 (2020). https://doi.org/10.1038/s41565-020-0636-2
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