Nature communicationsJan 17, 2026

Flexible and reliable DNA base editing using paired protein parts that join together

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 18, 2026

Abstract

A maximum editing efficiency enhancement of 12.4-fold was observed in primary somatic cells using coiled-coil heterodimers-mediated base editors.

Base editors are limited by their size, which exceeds the packaging capacity of adeno-associated virus.
A split base editor system was designed to enhance in vivo applications by recruiting deaminases to Cas9 nickase.
Various base editors, including cytidine (CC-CBE) and adenine (CC-ABE), were developed with maintained or improved editing efficiency.
Editing efficiency improvements were noted across different cell types, with a maximum of 9.6-fold in human immortalized cells.
In vivo editing was validated using dual-AAV vectors, successfully achieving A-to-G conversion in specific genes in mice.

Simplified

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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Competing interests

Competing interests: The authors declare no competing interests.

PubMed

Flexible and reliable DNA base editing using paired protein parts that join together

Abstract

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Abstract

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Funding

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Related papers

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Recent issues from the crispr gene editing brief