Coiled-coil heterodimer-mediated split base editing systems enable flexible and robust nucleotide substitutions
Brief intro:
- Author: Shuangshuang Mu, Qianru Li, Menglong Chen, Ziqi Li, Yuke Ma, Yuqi Li, Yiran Song, Shuangying Hou, Yuting Ding, Jialu Ju, Yue Lin, Jian Zhang, Yuanxi Yang, Xue Ren, Nan Li, Qin Jin, Liangxue Lai, Kepin Wang, Hui Shi
- Journal: Nature Communications
- Doi: https://www.doi.org/10.1038/s41467-026-68469-2
- Publication Date: 2026/1/17
Abstract
Base editors (BEs) enable precise base substitutions, but their size exceeds the packaging capacity of adeno-associated virus (AAV), impeding in vivo applications. Here we design a split BE system that recruits deaminases to Cas9 nickase via coiled-coil heterodimers, resulting in various coiled-coil heterodimers-mediated base editors (CC-BEs), including cytidine base editor (CC-CBE), adenine base editor (CC-ABE), and their derivatives. We reveal that CC-BEs maintain and even improve the editing efficiency of the original unsplit BEs across various cell types and editing scopes, achieving maximum enhancements of 9.6-fold in human immortalized cells and 12.4-fold in primary somatic cells for CC-CBE. Using CC-ABE, we validate in vivo editing efficiency and successfully achieve A-to-G conversion in the Pcsk9 and Dmd genes via dual-AAV vectors in mice. Altogether, we develop a simple and universal strategy to address the challenges posed by the large size of BEs without compromising editing efficiency for base substitutions in vivo.
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