Regulating extracellular vesicle trafficking and intercellular communications with photo-reversible viscoelastic hydrogels

Extracellular vesicle (EV) mediated intercellular communication determines various physiological and pathological processes that show great potential as therapeutic reagents. While EV trafficking through extracellular matrix (ECM) is influenced by both vesicle deformation and medium re-organization or viscoelasticity, how matrix mechanics regulates EV intercellular transportation remains unclear. In this work, we introduced a photo-tunable hydrogel platform as ECM mimicry that allows well-defined viscoelasticity changes of the matrix to manipulate EV trafficking. The light-responsive dynamic bond formation/disruption in hydrogel triggers a sharp transformation of hydrogel between fast stress relaxation (ca. 50 s) and slow stress relaxation (> 1000 s) states. Such large viscoelasticity discrepancy leads to a varied transportation rate of EVs (ca. 2-fold) and consequential programmed cellular migration behaviors to the recipient fibroblast NIH-3T3 cells through photo-responsive hydrogel platform. Furthermore, using model membrane systems, we revealed how membrane rigidity and ECM viscoelasticity contribute together during EV intercellular trafficking.