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Closed-loop systems designed to self-regulate in response to abnormal biomarker levels are particularly attractive for biomedical applications. In this study, we engineered PRO (phenylalanine regulation orchestration), a cell-autonomous genetic system capable of sensing and degrading elevated levels of phenylalanine, an essential amino acid that accumulates to pathological levels in patients with phenylketonuria (PKU). Central to this system is a transcriptional switch relying on the regulatory domain of human phenylalanine hydroxylase, which dimerizes in the presence of phenylalanine to reconstitute a split transcription factor, thereby inducing gene expression from a synthetic promoter. This sensing module was optimized through random mutagenesis to ensure responsiveness to high concentrations of phenylalanine, enabling robust and dose-dependent activation of protein expression. Engineered human PRO cells containing the sensor driving the expression of phenylalanine-degrading enzymes effectively detected and degraded excess phenylalanine. Microencapsulated PRO cells efficiently reduced phenylalanine levels to the normal physiological range when cultured in human whole blood. Finally, as proof of concept, we showed that alginate-encapsulated PRO cells intraperitoneally implanted in a PKU mouse model significantly lowered blood phenylalanine levels compared to controls implanted with non-engineered cells. Our results suggest that synthetic self-regulating systems are promising candidates for the treatment of metabolic diseases characterized by accumulation of toxic metabolites.<\/jats:p>","DOI":"10.1093\/nar\/gkaf1151","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T12:20:58Z","timestamp":1760530858000},"source":"Crossref","is-referenced-by-count":5,"title":["Synthetic closed-loop gene circuit for phenylalanine regulation"],"prefix":"10.1093","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7977-3986","authenticated-orcid":false,"given":"Silvia","family":"Galvan","sequence":"first","affiliation":[{"name":"ETH Zurich Department of Biosystems Science and Engineering, , Klingelbergstrasse 48, Basel CH-4056 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Qing","family":"Xie","sequence":"additional","affiliation":[{"name":"ETH Zurich Department of Biosystems Science and Engineering, , Klingelbergstrasse 48, Basel CH-4056 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana P","family":"Teixeira","sequence":"additional","affiliation":[{"name":"ETH Zurich Department of Biosystems Science and Engineering, , Klingelbergstrasse 48, Basel CH-4056 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8545-667X","authenticated-orcid":false,"given":"Martin","family":"Fussenegger","sequence":"additional","affiliation":[{"name":"ETH Zurich Department of Biosystems Science and Engineering, , Klingelbergstrasse 48, Basel CH-4056 ,","place":["Switzerland"]},{"name":"Faculty of Science, University of Basel , Klingelbergstrasse 48, Basel CH-4056 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