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Here, we aimed to engineer a cell-based system to sense cardiac troponin I (cTnI), an early marker of acute myocardial infarction (AMI), and respond by releasing a thrombolytic agent. To detect cTnI, we engineered a chimeric troponin receptor (TropR) that contains extracellular single-chain variable fragments (scFvs) and signals via intracellular domains of interleukin 6 receptor subunit beta (IL6RB), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor receptor 2b (FGFR2b) or vascular endothelial growth factor receptor 2 (VEGFR2) that are associated with cardioprotective signaling. cTnI-dependent TropR functionality was confirmed in human embryonic kidney (HEK)-derived cell lines as well as iPSC-derived cardiomyocytes, and enabled rapid, reversible, tunable control of gene expression via synthetic-signaling-specific promoters. We then constructed monoclonal cell lines for cTnI-induced secretion of the thrombolytic protein tenecteplase (TNK), together with an off-switch triggered by FDA-approved doxycycline. We selected a clone, designated CardioProtect, whose sensitivity was optimized to detect human AMI-relevant cTnI levels. To validate thrombolytic efficacy, we established an ex vivo blood culture system and show that alginate-microencapsulated CardioProtect cells triggered complete lysis of fibrin clots in a strict cTnI-inducible, doxycycline-repressible manner. This closed-loop strategy serves as a proof-of-concept for using cell therapy in the early detection and treatment of AMI.<\/jats:p>","DOI":"10.1038\/s44320-025-00161-x","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T12:53:08Z","timestamp":1760100788000},"page":"88-101","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Engineering mammalian cells for detection and treatment of cardiac injury"],"prefix":"10.1038","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7622-1908","authenticated-orcid":false,"given":"Yaqing","family":"Si","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5665-5669","authenticated-orcid":false,"given":"Yuxuan","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2490-4015","authenticated-orcid":false,"given":"Leo","family":"Scheller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3829-1979","authenticated-orcid":false,"given":"Bozhidar-Adrian","family":"Stefanov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1800-2384","authenticated-orcid":false,"given":"Zhihua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5657-532X","authenticated-orcid":false,"given":"Mingqi","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8545-667X","authenticated-orcid":false,"given":"Martin","family":"Fussenegger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"161_CR1","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1007\/s12079-016-0352-8","volume":"10","author":"CS Abhinand","year":"2016","unstructured":"Abhinand CS, Raju R, Soumya SJ, Arya PS, Sudhakaran PR (2016) VEGF-A\/VEGFR2 signaling network in endothelial cells relevant to angiogenesis. 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