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<p>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 <i>mPcsk9</i> and 64.2% at <i>mHpd</i> in the liver, as well as 24.2% at <i>mVegfa</i> 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.</p>

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Efficient in vivo cytosine base editing using virus-like particles with uracil DNA glycosylase inhibition

  • 期刊论文

  • 发表日期：

    2026年7月10日

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  • Junjie Zhu,
  • Lin Ding,
  • Kai-Ming Liu,
  • Xingyu Zhu,
  • Jifang Li,
  • Buer Ha,
  • Bao-Qing Gao,
  • Xujiao Zhou,
  • Chengfang Liu,
  • Jia Wei,
  • Shuangyu Ma,
  • Wenchao Xu,
  • Lingyun Kong,
  • Jing Wu,
  • Xiaodun Mou,
  • Bei Yang,
  • Lijie Wang,
  • Jiaxu Hong,
  • Li Yang,
  • Jia Chen

摘要

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.