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The recently developed transformer base editor (tBE) significantly reduces both genomic and transcriptomic OT mutations by using a cleavable deoxycytidine deaminase inhibitor (dCDI) domain. However, the modest base editing efficiency limits its broader applications. Here, through rational deaminase engineering and fusion of a uracil DNA glycosylase inhibitor (UGI) domain, we developed the engineered tBE (etBE). The etBE exhibited substantially enhanced editing efficiencies compared with the parental tBE (up to 35.11\u2010fold improvement), while maintaining high editing fidelity and background levels of OT mutations. As a therapeutic proof\u2010of\u2010concept, dual adeno\u2010associated virus (AAV)\u2010mediated delivery of etBE targeting proprotein convertase subtilisin\/kexin type 9 (\n                    <jats:italic>PCSK9<\/jats:italic>\n                    ), a well\u2010established therapeutic target for cardiovascular diseases, was evaluated in a humanized mouse model. The treatment achieved efficient in vivo base editing (up to 35.13%), resulting in substantial reductions in plasma PCSK9 protein (24%) and low\u2010density lipoprotein cholesterol (LDL\u2010C) levels (33%), while inducing only minimal OT mutations. Collectively, etBE represents a highly efficient and specific base editing platform with enormous potential for both basic research and clinical applications.\n                  <\/jats:p>","DOI":"10.1002\/advs.77657","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T04:34:42Z","timestamp":1789101282000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineered Transformer Base Editor with Enhanced Editing Efficiency"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5613-6921","authenticated-orcid":false,"given":"Bowen","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Genetics and Development of Complex Phenotypes and MOE Engineering Research Center of Gene Technology, School of Life Sciences, and Taizhou Institute of Health Science Fudan University  Shanghai People's Republic of 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