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However, EV\u2010based therapeutics remain constrained by inefficient cargo loading and low production yields, which limit scalable biomanufacturing. To overcome these limitations, we exploited the use of the mechanosensitive ion channel Piezo1 as a robust regulator of EV biogenesis using HEK293FT cells co\u2010transfected with Piezo1 and the bioluminescent EV reporter PalmReNL. Activation of Piezo1 with Yoda1 (30\u00a0\u00b5M) increased PalmReNL\u2010EV release by 3\u2010fold, while GsMTx4 inhibited EV release by 80.7%. This effect was unaffected by removal of extracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    but was suppressed by intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    chelation with BAPTA\u2010AM, indicating a reliance on intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    mobilisation. Small EVs (sEVs) from Piezo1\u2010activated cells were purified by anion exchange chromatography and analysed by proteomics, identifying 48 proteins exclusively in Piezo1\u2010induced sEVs preparations among 148 total detected, including cytoskeletal and stress\u2010related factors, while preserving enrichment of extracellular matrix (ECM) structural components prominent in both conditions. Yoda1 treatment increased the release of both large EVs (lEVs) and sEVs, with a particularly pronounced increase in sEV production. As a proof of concept for therapeutic cargo delivery, Yoda1 stimulation increased the incorporation of exogenously expressed interleukin\u201010 (IL\u201010) into sEVs by up to 4\u2010fold, and the bioactivity of sEV\u2010associated IL\u201010 was validated using IL\u201010\u2010CyCLoPs reporter cells. However, exposing Piezo1\u2010overexpressing cells to 30\u00a0\u00b5M Yoda1 markedly delayed cell adhesion and spreading, indicating that excessive Piezo1 activation may constrain sustained production of therapeutic sEVs. Collectively, these results identify mechanotransduction as a key regulator of sEV biogenesis and underscore the need for precise temporal control, potentially achievable through ultrasound\u2010based modulation, for the rational engineering of next\u2010generation sEV therapeutics.\n                  <\/jats:p>","DOI":"10.1002\/jex2.70182","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T18:35:22Z","timestamp":1788028522000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineering Piezo1\u2010Mediated Calcium Signalling for Enhanced Extracellular Vesicle Biogenesis and Cargo Loading"],"prefix":"10.1002","volume":"5","author":[{"given":"Najla A.","family":"Saleh","sequence":"first","affiliation":[{"name":"Institute for Quantitative Health Science and Engineering (IQ) Michigan State University  East Lansing Michigan 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Quantitative Health Science and Engineering (IQ) Michigan State University  East Lansing Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George I.","family":"Mias","sequence":"additional","affiliation":[{"name":"Institute for Quantitative Health Science and Engineering (IQ) Michigan State University  East Lansing Michigan USA"},{"name":"College of Natural Science Michigan State University  East Lansing Michigan USA"},{"name":"Department of Biochemistry and Molecular Biology Michigan State University  East Lansing Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangqing","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Immunology, Blavatnik Institute Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun R.","family":"Huh","sequence":"additional","affiliation":[{"name":"Department of Immunology, Blavatnik Institute Harvard Medical School  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