Extracellular vesicles (EVs) hold great promise in drug delivery, disease diagnosis, and treatment; however, the inability to control EVs biogenesis critically limits their therapeutic and diagnostic potential. Although regulatory mechanisms for biochemical cues have been extensively studied, the principles governing how diverse mechanical cues from the extracellular microenvironment orchestrate EV secretion are poorly understood, hindering the development of scalable production strategies. Here, we resolve this by introducing a theoretical model that identifies membrane reservoir depletion as a universal biophysical switch for EV release. We discover that EV secretion is directly activated by the depletion of the membrane reservoir and the consequent rise in membrane tension. This tension-mediated mechanism provides a unifying framework that reconciles disparate experimental observations under various biophysical perturbations, including cell spreading, osmotic shock, contractile perturbation, and substrate stiffening. Furthermore, we identify the membrane reservoir size as a key intrinsic parameter setting the threshold for mechanical activation of EV secretion, offering a rationale for engineering high-yield producer cell lines. Our work thus establishes a unifying mechanochemical framework for EV secretion, explaining disparate experimental observations and providing a quantitative design principle for optimizing EV production.

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• Cell mechanics
• Exocytosis
• Mechanotransduction
• Vesicles
• Multiscale modeling