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In spite of the growing demand for peptide therapeutics against infectious diseases, current small molecule\u2010based strategies still require frequent administration due to limited half\u2010life and enzymatic digestion in blood. To overcome this challenge, a strategy to continuously express multi\u2010level therapeutic peptide drugs on the surface of immune cells, is established. Here, chimeric T cells stably expressing therapeutic peptides are presented for treatment of severe infectious diseases. Using lentiviral system, T cells are engineered to express multi\u2010level therapeutic peptides with matrix metallopeptidases\u2010 (MMP\u2010) and tumor necrosis factor alpha converting enzyme\u2010 (TACE\u2010) responsive cleavage sites on the surface. The enzymatic cleavage releases \u03b3\u2010carboxyglutamic acid of protein C (PC\u2010Gla) domain and thrombin receptor agonist peptide (TRAP), which activate endothelial protein C receptor (EPCR) and protease\u2010activated receptor\u20101 (PAR\u20101), respectively. These chimeric T cells prevent vascular damage in tissue\u2010engineered blood vessel and suppress hypercytokinemia and lung tissue damages in vivo, demonstrating promise for use of engineered T cells against sepsis and other infectious\u2010related diseases.<\/jats:p>","DOI":"10.1002\/advs.202201883","type":"journal-article","created":{"date-parts":[[2022,6,25]],"date-time":"2022-06-25T04:25:44Z","timestamp":1656131144000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cleavage\u2010Responsive Biofactory T Cells Suppress Infectious Diseases\u2010Associated Hypercytokinemia"],"prefix":"10.1002","volume":"9","author":[{"given":"Hyelim","family":"Kim","sequence":"first","affiliation":[{"name":"Brain Science Institute Korea Institute of Science and Technology (KIST)  Seoul 02792 Republic of Korea"},{"name":"Department of Biotechnology Yonsei University  Seoul 03722 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boram","family":"Son","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Hanyang University  Seoul 04763 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun U","family":"Seo","sequence":"additional","affiliation":[{"name":"Brain Science Institute Korea Institute of Science and Technology (KIST)  Seoul 02792 Republic of Korea"},{"name":"Division of Bio\u2010Medical Science and Technology (KIST School) Korea University of Science and Technology (UST)  Seoul 02792 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miji","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Smart Health Science and Technology Kangwon National University  Chuncheon 24341 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"June Hong","family":"Ahn","sequence":"additional","affiliation":[{"name":"Division of Pulmonology and Allergy Department of Internal Medicine College of Medicine Yeungnam University and Regional Center for Respiratory Diseases Yeungnam University Medical Center  Daegu 42415 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heungsoo","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Hanyang University  Seoul 04763 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gyu Yong","family":"Song","sequence":"additional","affiliation":[{"name":"College of Pharmacy Chungnam National University  Daejeon 34134 Republic of Korea"},{"name":"AREZ Co. Ltd  Daejeon 34134 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun Ji","family":"Park","sequence":"additional","affiliation":[{"name":"D&amp;D Pharmatech  Seongnam 13486 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong Hee","family":"Na","sequence":"additional","affiliation":[{"name":"College of Pharmacy Chung\u2010Ang University  Seoul 06974 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seung\u2010Woo","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Biotechnology Yonsei University  Seoul 03722 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0329-0029","authenticated-orcid":false,"given":"Hong Nam","family":"Kim","sequence":"additional","affiliation":[{"name":"Brain Science Institute Korea Institute of Science and Technology (KIST)  Seoul 02792 Republic of Korea"},{"name":"Division of Bio\u2010Medical Science and Technology (KIST School) Korea University of Science and Technology (UST)  Seoul 02792 Republic of Korea"},{"name":"School of Mechanical Engineering Yonsei University  Seoul 03722 Republic of Korea"},{"name":"Yonsei\u2010KIST Convergence Research Institute Yonsei University  Seoul 03722 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hee Ho","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Hanyang University  Seoul 04763 Republic of Korea"},{"name":"BK21 FOUR Education and Research Group for Biopharmaceutical Innovation Leader Hanyang University  Seoul 04763 Republic of Korea"},{"name":"Research Institute for Convergence of Basic Science Hanyang University  Seoul 04763 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wonhwa","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chemistry Sungkyunkwan University  Suwon 16419 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,6,25]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2109072"},{"key":"e_1_2_10_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(21)00558-2"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20060375"},{"key":"e_1_2_10_2_2","doi-asserted-by":"publisher","DOI":"10.4161\/viru.27045"},{"key":"e_1_2_10_2_3","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-018-2052-7"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30628-0"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(20)30161-2"},{"key":"e_1_2_10_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(20)30165-X"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30183-5"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2017.06.052"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2011.09.092"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200103083441009"},{"key":"e_1_2_10_8_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-09-003004"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)47415-2"},{"key":"e_1_2_10_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb01073.x"},{"key":"e_1_2_10_10_1","unstructured":"U. 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