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Patients diagnosed with type\u2010I diabetes mellitus experience chronic and remarkably high blood\u2010sugar levels, and require lifelong insulin injection therapy, so there is a need for more convenient and less invasive insulin delivery systems to increase patients\u2019 compliance and also to enhance their quality of life. Here, an endoplasmic\u2010reticulum\u2010localized split sec\u2010tobacco etch virus protease (TEVp)\u2010based rapamycin\u2010actuated protein\u2010induction device (RAPID) is engineered, which is composed of the rapamycin\u2010inducible dimerization domains FK506 binding protein (FKBP) and FKBP\u2010rapamycin binding protein fused with modified split sec\u2010TEVp components. Insulin accumulation inside the endoplasmic reticulum (ER) is achieved through tagging its C\u2010terminus with KDEL, an ER\u2010retention signal, spaced by a TEVp cleavage site. In the presence of rapamycin, the split sec\u2010TEVp\u2010based RAPID components dimerize, regain their proteolytic activity, and remove the KDEL retention signal from insulin. This leads to rapid secretion of accumulated insulin from cells within few minutes. Using liver hydrodynamic transfection methodology, it is shown that RAPID quickly restores glucose homeostasis in type\u20101\u2010diabetic (T1DM) mice treated with an oral dose of clinically licensed rapamycin. This rapid\u2010release technology may become the foundation for other cell\u2010based therapies requiring instantaneous biopharmaceutical availability.<\/jats:p>","DOI":"10.1002\/advs.202105619","type":"journal-article","created":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T03:19:48Z","timestamp":1642648788000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Engineering a Rapid Insulin Release System Controlled By Oral Drug Administration"],"prefix":"10.1002","volume":"9","author":[{"given":"Mohamed","family":"Mahameed","sequence":"first","affiliation":[{"name":"Department of Biosystems Science and Engineering ETH Zurich  Mattenstrasse 26 Basel CH\u20104058 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Biosystems Science and Engineering ETH Zurich  Mattenstrasse 26 Basel CH\u20104058 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