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However, existing Cas13-mediated translational activation systems are limited by modest potency and restricted modular expandability. Here, we developed the Enhanced Targeted Translational Activation System (ETTAS), a modular RNA-guided platform that combines dCas13a, the SINEB2 translational activation element, and an independently recruitable aptamer-mediated auxiliary module. Systematic ortholog screening identified dCas13a as the most effective scaffold for SINEB2-mediated translational activation, whereas direct tandem duplication of SINEB2 elements impaired rather than enhanced activity. To overcome this architectural limitation, we used aptamer-mediated recruitment to spatially separate target recognition from auxiliary activation. A binding-validated, non-interfering dCas13a-binding aptamer enabled construction of a dual-module system in which an aptamer-recruited SINEB2 element enhanced translation without altering target mRNA abundance or stability. Compared with the previously reported dCasRx\u2013SINEB2 system, ETTAS produced stronger reporter activation, stronger endogenous induction of P53 and PTEN, and greater antiproliferative and pro-apoptotic effects in bladder cancer cells. Proteomic analyses showed selective target protein upregulation with limited global perturbation. In vivo, dual-AAV delivery of ETTAS activated endogenous P53 and suppressed tumor growth. ETTAS establishes a programmable framework for modular post-transcriptional upregulation of endogenous proteins.<\/jats:p>","DOI":"10.1093\/nar\/gkag692","type":"journal-article","created":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T07:57:26Z","timestamp":1784966246000},"source":"Crossref","is-referenced-by-count":0,"title":["ETTAS: a modular aptamer-recruited platform for programmable translational activation"],"prefix":"10.1093","volume":"54","author":[{"given":"Aolin","family":"Li","sequence":"first","affiliation":[{"name":"Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People\u2019s Hospital , Shenzhen 518035 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Central Laboratory, Shenzhen Bao\u2019an District Songgang People\u2019s Hospital , Shenzhen 518035 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Senmao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Affiliated Hospital of Kunming Medical University , Kunming 650101 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Wuhan No. 1 Hospital, Wuhan Hospital of Traditional Chinese and Western Medicine , Wuhan 430065 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9609-1848","authenticated-orcid":false,"given":"Chaojie","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Urology, Peking University First Hospital , Beijing 100034 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changning","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Urology, Peking University First Hospital , Beijing 100034 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Hubei University of Chinese Medicine, Hubei Shizhen Laboratory , Wuhan 430065 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6517-0022","authenticated-orcid":false,"given":"Yuchen","family":"Liu","sequence":"additional","affiliation":[{"name":"Shenzhen Institute of Translational Medicine, Shenzhen Second People\u2019s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen University , Shenzhen 518035 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxia","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Urology, The First People\u2019s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology , Kunming 650032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3895-921X","authenticated-orcid":false,"given":"Congcong","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Hubei University of Chinese Medicine, Hubei Shizhen Laboratory , Wuhan 430065 ,","place":["China"]},{"name":"Shenzhen Institute of Translational Medicine, Shenzhen Second People\u2019s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen University , Shenzhen 518035 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