Nature biotechnologyJul 10, 2026

Efficient cytosine base editing inside living cells using virus-like particles that block uracil DNA repair

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 14, 2026

Abstract

tBE-VLPs achieved an average of 46.0% editing at mPcsk9 and 64.2% at mHpd in the mouse liver.

Insufficient inhibition of uracil DNA glycosylases is linked to low editing efficiencies of cytosine base editors in living organisms.
An engineered transformer base editor (tBE) was developed alongside a virus-like particle (VLP) delivery system to improve the editing process.
Robust C-to-T editing was observed in mouse liver and retina using the tBE-VLP system.
A single injection of tBE-VLPs resulted in editing rates of 24.2% at mVegfa in the retinal pigment epithelium.
tBE-VLP4 showed no detectable off-target edits in both laboratory and living systems, indicating high precision and specificity.

Simplified

Virus-like particles (VLPs) are promising for delivering genome editors, yet the in vivo in vivo efficacy of VLP-mediated cytosine base editing remains limited. Here we identified insufficient inhibition of uracil DNA glycosylases as the underlying mechanism of low cytosine base editor (CBE) editing efficiencies in vivo. We engineered a previously reported CBE, transformer base editor (tBE), and developed a VLP delivery system to enhance the recruitment of uracil DNA glycosylase inhibitor proteins. tBE-VLPs achieved robust C-to-T editing in mouse liver and retina. A single injection achieved, on average, 46.0% editing at mPcsk9 and 64.2% at mHpd in the liver, as well as 24.2% at mVegfa in the retinal pigment epithelium, resulting in marked therapeutic benefits in mouse disease models. tBE-VLP4 induced no detectable off-target edits in vitro or in vivo and demonstrated superior specificity compared to AAV or lipid nanoparticle mRNA delivery. Our work establishes tBE-VLP4 as a precise, efficient system for in vivo cytosine base editing.

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Funding

Competing interests

Competing interests: J.C., L.Y. and B.Y. are scientific cofounders of CorrectSequence Therapeutics (a company that uses gene-editing technologies) and members of its scientific advisory board. J.C., L.Y., B.Y., J.Z., L.D. and J.L. have filed patent applications related to the published work through ShanghaiTech University. The other authors declare no competing interests.

PubMed

Efficient cytosine base editing inside living cells using virus-like particles that block uracil DNA repair

Abstract

Full Text

Funding

Competing interests

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