Biophysical modulation of stem cell- derived extracellular vesicles

Stem cell-derived extracellular vesicles (EVs) show considerable potential for regenerative medicine. However, their translation is limited by variability in production, cargo composition, and function. Conventional culture conditions influence EV yield and biomolecular composition, but recent studies demonstrate that mechanical cues and biophysical forces during stem cell culture are also critical regulators of EV biogenesis and cargo loading. Here, we review advances in understanding stem cell mechanosensitivity and how modulation of three-dimensional (3D) microenvironments such as matrix stiffness and viscoelasticity, as well as the application of mechanical forces can influence EV production and functional potential, while also discussing potential underlying mechanisms. The aim of this review is to define key parameters for advancing control of EV modulation through mechanical cues which could extensively enhance their potential as therapeutic tools.