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Most CAR\u2010Treg programs still use single\u2010chain variable fragments (scFvs) derived from monoclonal antibodies optimized for effector function, a bias that may promote CAR clustering, tonic signaling, and lineage instability. Here, we propose a phage\u2010first binder discovery framework for CAR\u2010Tregs and state testable hypotheses linking phage\u2010display selection pressures to scFv biophysical properties and Treg fate. We hypothesize that multi\u2010parameter selection and counter\u2010selection can enrich scFvs with moderate affinity, low polyspecificity, and improved framework stability, thereby lowering tonic signaling in defined backbone architectures and preserving FOXP3\/TSDR stability under inflammatory stress. We outline a falsifiable two\u2010phase roadmap\u2014bench triage followed by mechanistic and preclinical validation to determine how scFv properties, expression level, and intracellular signaling domains define an optimal tonic window for durable immune regulation.<\/jats:p>","DOI":"10.1002\/bies.70164","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T05:46:48Z","timestamp":1784180808000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineering CAR\u2010Tregs with Phage\u2010Selected scFv Enables a New Paradigm for Immune Regulation"],"prefix":"10.1002","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6250-8692","authenticated-orcid":false,"given":"Fatih","family":"Noyan","sequence":"first","affiliation":[{"name":"Dept. of Gastroenterology Hepatology, Infectious Disease and Endocrinology Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2827-7787","authenticated-orcid":false,"given":"Matthias","family":"Hardtke\u2010Wolenski","sequence":"additional","affiliation":[{"name":"Dept. of Gastroenterology Hepatology, Infectious Disease and Endocrinology Hannover Medical School  Hannover Germany"},{"name":"Inst. of Medical Microbiology University Hospital Essen University Duisburg\u2010Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.188624"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2023.11.005"},{"key":"e_1_2_7_4_1","unstructured":"ClinicalTrials.gov TX200\u2010TR101 in HLA\u2010A2\u2013mismatched Kidney Transplantation (STEADFAST) NCT04817774(U.S. National Library of Medicine 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