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As a first step toward meeting this challenge, we adapted a synthetic Notch (SynNotch) receptor system to report force transmission through immunoreceptors in vivo by replacing the native ligand\u2010binding domain with a receptor\u2010specific antibody and rewiring Notch signaling to drive enhanced green fluorescent protein or luciferase expression. We expressed SynNotch on Jurkat cells targeting CD40 or T cell receptor (TCR) and characterized their activation in coculture with B or T cells, defining the requirements, optimal conditions, and kinetics of activation. Using complementary mechanobiology approaches, we quantified the exogenous force required for reporter activation and verified that activation depends on forces generated by receptor\u2010expressing sender cells rather than SynNotch\u2010expressing receiver cells. By implanting sensors and targets into immunocompromised mice, we visualized mechanically activated reporter expression on CD40 and TCR\u2010targeting SynNotch cells in vivo. Furthermore, CD40 and TCR signaling was amplified when the receptor bore force against mechanical support from immobilized ligand, indicating that force functions as a biologically relevant co\u2010stimulus. Together, our results establish mechanically activated SynNotch reporters as a useful strategy for detecting receptor\u2010associated mechanical signaling across two\u2010dimensional\u00a0coculture, three\u2010dimensional\u00a0organoid, and in vivo systems.<\/jats:p>","DOI":"10.1002\/advs.77318","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T15:41:52Z","timestamp":1787672512000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SynNotch Receptors for Visualizing Immunoreceptor Force Transmission and Downstream Signaling In Vivo"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5248-5433","authenticated-orcid":false,"given":"Menglan","family":"Li","sequence":"first","affiliation":[{"name":"Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"Parker H. Petit Institute for Bioengineering and Biosciences Georgia Institute of Technology  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintian","family":"Lyu","sequence":"additional","affiliation":[{"name":"Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"Parker H. Petit Institute for Bioengineering and Biosciences Georgia Institute of Technology  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitao","family":"Li","sequence":"additional","affiliation":[{"name":"Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"Parker H. Petit Institute for Bioengineering and Biosciences Georgia Institute of Technology  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ameya","family":"Dravid","sequence":"additional","affiliation":[{"name":"Parker H. Petit Institute for Bioengineering and Biosciences Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"George W. Woodruff School of Mechanical Engineering Georgia Institute of Technology  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2848-9288","authenticated-orcid":false,"given":"Deepali","family":"Balasubramani","sequence":"additional","affiliation":[{"name":"Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"Parker H. Petit Institute for Bioengineering and Biosciences Georgia Institute of Technology  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7441-2927","authenticated-orcid":false,"given":"Amir H.","family":"K. Ashkezari","sequence":"additional","affiliation":[{"name":"Parker H. Petit Institute for Bioengineering and Biosciences Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"George W. Woodruff School of Mechanical Engineering Georgia Institute of Technology  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9192-891X","authenticated-orcid":false,"given":"Hyun\u2010Kyu","family":"Choi","sequence":"additional","affiliation":[{"name":"Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"Parker H. Petit Institute for Bioengineering and Biosciences Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"Department of Biochemistry College of Life Science and Biotechnology Yonsei University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel A.","family":"Kwong","sequence":"additional","affiliation":[{"name":"Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"Parker H. Petit Institute for Bioengineering and Biosciences Georgia Institute of Technology  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3501-2277","authenticated-orcid":false,"given":"Ankur","family":"Singh","sequence":"additional","affiliation":[{"name":"Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"Parker H. Petit Institute for Bioengineering and Biosciences Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"George W. Woodruff School of Mechanical Engineering Georgia Institute of Technology  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1718-565X","authenticated-orcid":false,"given":"Cheng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"Parker H. Petit Institute for Bioengineering and Biosciences Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"George W. 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