Enhancing EV-cell communication through "External Modulation of Cell by EV" (EMCEV).

Mesenchymal stem/stromal cells (MSC) have displayed promising therapeutic potential. Nonetheless, no United States Food and Drug Administration (FDA)-approved MSC product exists due largely to the absence of a reliable potency assay based on the mechanisms of action to ensure consistent efficacy. MSCs are now thought to exert their effects primarily by releasing small extracellular vesicles (sEVs) of 50-200 nm. While non-living MSC-sEV drugs offer distinct advantages over larger, living MSC drugs, elucidating their mechanism of action to develop robust potency assays remains a challenge. A pivotal prelude to elucidating the mechanism of action for MSC-sEVs is how extracellular vesicles (EVs) engage their primary target cells. Given the inherent inefficiencies of processes such as endocytosis, endosomal escape and EV uncoating during cellular internalization, we propose an alternative EV-cell engagement: EMCEV (Extracellular Modulation of Cells by EV). This approach involves extracellular modulation by EV attributes to generate signaling/inhibitory molecules that have the potential to affect many cells within the vicinity, thereby eliciting a more widespread tissue response.