High Efficiency Production of Functional Small Extracellular Vesicles through Cellular Self-Motivation

In stem cell therapies, small extracellular vesicles (sEVs) are extremely limited in application due to their limited production. Here, we propose a new concept of "cellular self-stimulation" and develop a cost-effective method for the preparation of sEVs, which enables the conversion of cellular traction to self-generated stimulation through piezoionic hydrogels and enhances the ability of cells to secrete sEVs by more than an order of magnitude. The traction of the adherent cells leads to deformation of the piezoionic substrate, which in turn translates into a millivolt-level electrical signal acting on the cell itself, stimulating the cell to produce more sEVs. These sEVs remain biologically intact and have shown excellent efficacy in in vitro and in vivo assays, confirming the superior therapeutic potential of high concentrations of sEVs. This provides a strong impetus for the development and dissemination of stem cell therapies.