{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:12:19Z","timestamp":1788541939469,"version":"build-2803163510"},"reference-count":34,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32101168"],"award-info":[{"award-number":["32101168"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32101168"],"award-info":[{"award-number":["32101168"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Research Talents Program of The First Affiliated Hospital, Sun Yat-sen University","award":["Y61232"],"award-info":[{"award-number":["Y61232"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Small-molecule-regulated gene switches are important tools for programmable mammalian cell engineering, and compact switches responsive to clinically familiar ligands that can be administered locally are particularly attractive for externally regulated transgene expression. Methods: Here, we developed ZF10\u2013\u0394VDR, a compact zinc-finger\u2013VDR transcriptional switch, by fusing an orthogonal human-derived zinc-finger array, ZF10, to the hinge and ligand-binding domain of the vitamin D receptor. The resulting switch enabled transgene regulation by calcipotriol, a clinically used topical vitamin D analog and VDR agonist. Results: ZF10\u2013\u0394VDR maintained low basal activity, showed limited activation by the tested vitamin D species at physiologically relevant reference concentrations, and was robustly activated by calcipotriol. The system functioned across multiple human cell types. In vivo, topical calcipotriol increased serum reporter output in mice bearing subcutaneous microencapsulated-cell implants, whereas oral vitamin D3 did not measurably activate this system under the tested conditions. In a separate HaCaT implantation model, topical calcipotriol increased bioluminescence at wound-adjacent implantation sites. ZF10\u2013\u0394VDR also supported reversible ON\/OFF cycling under the tested conditions and inducible secreted protein output in vitro. Conclusions: These findings establish ZF10\u2013\u0394VDR as a calcipotriol-responsive switch with limited activation by endogenous vitamin D species, activity across multiple mammalian cell types, reversible regulation under the tested conditions, and compatibility with topical induction in vivo.<\/jats:p>","DOI":"10.3390\/genes17091072","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T16:07:32Z","timestamp":1788538052000},"page":"1072","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Calcipotriol-Responsive ZF10\u2013\u0394VDR Switch for Mammalian Transgene Regulation with Topical Induction In Vivo"],"prefix":"10.3390","volume":"17","author":[{"given":"Hong","family":"Su","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China"},{"name":"Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Shiting","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China"},{"name":"Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Fudan University, Shanghai 200438, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Guanyang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China"},{"name":"Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0141-0573","authenticated-orcid":false,"given":"Peng","family":"Bai","sequence":"additional","affiliation":[{"name":"Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1038\/s41580-018-0024-z","article-title":"Designing cell function: Assembly of synthetic gene circuits for cell biology applications","volume":"19","author":"Xie","year":"2018","journal-title":"Nat. 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