翌圣生物 Yeasen｜生命科学试剂与诊断原料一站式平台

Abstract

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.