Minimizing the ratio of ionizable lipid in lipid nanoparticles for in vivo base editing

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外文摘要：Lipid nanoparticles(LNPs)have gained clinical approval as carriers for both siRNA and mRNA.Among the crucial components of LNPs,ionizable lipids play a pivotal role in determining the efficiency of RNA delivery.In this study,we synthesized a series of ionizable lipids,denoted as HTO,with a higher count of hydroxyl groups compared to SM-102.Remarkably,LNPs based on HTO 12 lipid demonstrated comparable mRNA delivery efficiency and biosafety to those based on SM-102.However,the former reduced the ratio of ionizable lipid/total lipids to mRNA in LNPs by 2.5 times compared to SM-102.The HTO 12 LNP efficiently encapsulated adenine base editor mRNA and sgRNA targeting Pcsk9,leading to substantial gene editing within the liver of mice and effective reduction of the target protein.Our study underscores that ionizable lipids with multiple hydroxyl groups may facilitate an improved lipid-to-mRNA ratio to minimize the dosage of ionizable lipids for in vivo delivery.

外文关键词：

ionizable lipidlipid nanoparticlemRNA deliverybase editor deliveryPcsk9

作者：

Qiubing Chen、Xuebin Wang、Yizhou Zhang、Ming Tian、Junyi Duan、Ying Zhang、Hao Yin

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作者单位：

Departments of Urology and Laboratory Medicine,Frontier Science Center for Immunology and Metabolism,Medical Research Institute,Zhongnan Hospital of Wuhan University,Wuhan University,Wuhan 430071,China

State Key Laboratory of Virology,TaiKang Center for Life and Medical Sciences,TaiKang Medical School,Wuhan University,Wuhan 430071,China

Department of Rheumatology and Immunology,Zhongnan Hospital of Wuhan University,Wuhan University,Wuhan 430071,China

Wuhan Research Center for Infectious Diseases and Cancer,Chinese Academy of Medical Sciences,Wuhan 430071,China

RNA Institute,Wuhan University,Wuhan 430071,China

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基金：

National Key R&D Program of ChinaNational Key R&D Program of ChinaNational Key R&D Program of ChinaKey R&D Program of Hubei ProvinceKey R&D Program of Hubei ProvinceMinistry of Agriculture and Rural Affairs of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaState Key Laboratory for Animal Disease Control and PreventionMedical Science Advancement Program(Basic Medical Sciences)of Wuhan UniversityFundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central UniversitiesApplied Basic Frontier Program of Wuhan Citystartup funding from Wuhan University

项目编号：

2019YFA08028012018YFA08014012022YFF10028012022BCA0892022ACA005318713453207144231972936SKLVBF202202TFJC20180042042022dx00032042022kf11902020020601012216

出版年：

2024

DOI：

10.1093/nsr/nwae135

国家科学评论(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.11(6)