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Various synthetic riboswitches have been engineered using in vitro-generated tetracycline and theophylline aptamers. However, many of these constructs exhibit suboptimal switching efficiency and background expression. Moreover, efforts to enhance their performance often involve time-consuming and costly screening processes. Here we report that artificial riboswitches can be efficiently optimized by engineering fusion aptamers that contain two binding pockets (apdimers). Following this rational approach, we generated cooperativity between both binding pockets, resulting in the improved performance of splicing-based and ribozyme-based synthetic riboswitches. We finally combined optimized tetracycline switches, yielding dynamic ranges exceeding 1000-fold with minimal background expression in the OFF state. In addition, we show that the optimized tetracycline riboswitches can be used to efficiently induce AAV-mediated transgene expression in mice. The presented strategy offers a straightforward and effective approach for the optimization of existing synthetic riboswitches and the design of novel riboswitches.<\/jats:p>","DOI":"10.1093\/nar\/gkag702","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T14:49:51Z","timestamp":1784040591000},"source":"Crossref","is-referenced-by-count":0,"title":["Engineering aptamer dimers (apdimers) for optimization of synthetic riboswitches"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0193-8697","authenticated-orcid":false,"given":"Vera","family":"Hedwig","sequence":"first","affiliation":[{"name":"Department of Chemistry, University of Konstanz , Konstanz 78457 ,","place":["Germany"]},{"name":"Konstanz Research School Chemical Biology (KoRS-CB), University of Konstanz , Konstanz 78457 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8956-5942","authenticated-orcid":false,"given":"Elisabeth","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Konstanz , Konstanz 78457 ,","place":["Germany"]},{"name":"Konstanz Research School Chemical Biology (KoRS-CB), University of Konstanz , Konstanz 78457 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Ketterer","sequence":"additional","affiliation":[{"name":"Research Beyond Borders, Boehringer Ingelheim Pharma GmbH & Co. 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