Cells produce nano-sized particles composed of a phospholipid bilayer, which are commonly referred to as extracellular vesicles (EVs). Though observed and described for many decades, these particles have often been thought of as waste vehicles but are now increasingly being extensively studied as means for cells to communicate with each other under physiological conditions as well as during the development or progression of diseases. Notably, EVs are also emerging as a potential cell-free therapeutic targeting some inflammatory diseases and have already shown efficacy in some preclinical disease models .
One of the challenges in the field of EV therapeutics is developing approaches that allow for precise dosing and delivery of EVs. Our group therefore initially focused on developing hydrogel materials that would allow for controlled delivery of therapeutic EVs to diseased tissues. Because the polymer matrix comprising hydrogels typically exhibits a nanoporous mesh size much smaller than EVs, we thought that EVs would not be able to transport within hydrogels, and thus the materials would require engineered modifications that allow EV transport. We surmised that some natural matrices could also be dense enough that they would trap secreted EVs. Indeed, a growing field of research describes the presence of EVs in decellularized tissues [2,3]. However, to avoid potential issues related to extensive EV accumulation within tissues, it seemed likely to us that there had to be some mechanisms that would allow EVs to transport through the ECM. We were intrigued by the question of how EVs could possibly navigate a matrix with a mesh smaller than their own size.
To our surprise, EVs transported within decellularized extracellular matrix tissue as well as within our synthetic hydrogel matrices. Because we also found that similarly sized synthetic nanoparticles and liposomes were not able to transport through the same matrix, we hypothesized that EVs possess a unique biological property enabling their transport through a dense mesh. After teasing out potential mechanisms, we eventually discovered that the water channel aquaporin-1 present on EVs mediates their ability to deform, thereby overcoming spatial confinement.
We believe that these insights represent a further demonstration that EVs are likely not simple cellular waste products, but instead may be evolved to carry and deliver contents through their extracellular environment. Our results will also likely prompt further investigations into both physiological mechanisms of EV transport and how EVs disperse in diseased tissues with altered physical properties such as scarred tissues and tumors. Ultimately, we hope that these new insights into EV transport could significantly enhance the prospects of using EVs to deliver therapeutics in a wide range of patients.
The full paper can be accessed through the link below:
1. Wiklander, O. et al. Advances in therapeutic applications of extracellular vesicles. Science Translational Medicine. 11, (2019).
2. Huleihel, L. et al. Matrix-bound nanovesicles within ECM bioscaffolds. Science Advances 2(6), e1600502 (2016).
3. Rilla, K. et al. Extracellular vesicles are integral and functional components of the extracellular matrix. Matrix Biology 75–76, 201–219 (2019).