ADAM10 tailors extracellular vesicles for content transfer rather than signaling by contact

Etxtracellular vesicles (EVs) support cell-to-cell communication, both in physiological and pathological contexts and emerge as new biomarkers and potential therapeutics. Yet, despite EVs holding huge promises, our understanding of core mechanisms governing EV signaling remains significantly underdeveloped. Our previous work indicated that syndecans and their cytosolic adaptor syntenin control the biogenesis of a major subset of small EVs (sEVs). Here we show that syndecans control the accumulation of ADAM10 into sEVs. ADAM10 promotes the formation of sEVs enriched in cleaved receptors (reducing sEV corona), supports the sorting of proteins with intracellular functions, and tailors sEVs for the delivery of their internal content, e.g. syntenin, into the cytosol of recipient cells. Conversely, inhibition of ADAM10 favors the production of sEVs bearing full-length, signaling-competent receptors/ligands and enhances contact-dependent signaling. These findings uncover a protease-regulated switch that tailors sEV composition and signaling modality, providing important new mechanistic insights into the core molecular pathways supporting EV-mediated communication.