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

作     者：Qiubing Chen Xuebin Wang Yizhou Zhang Ming Tian Junyi Duan Ying Zhang Hao Yin 

作者机构：Departments of Urology and Laboratory MedicineFrontier Science Center for Immunology and Metabolism Medical Research InstituteZhongnan Hospital of Wuhan UniversityWuhan University State Key Laboratory of VirologyTai Kang Center for Life and Medical Sciences Tai Kang Medical SchoolWuhan University Department of Rheumatology and ImmunologyZhongnan Hospital of Wuhan UniversityWuhan University Wuhan Research Center for Infectious Diseases and Cancer Chinese Academy of Medical Sciences RNA InstituteWuhan University 

出 版 物：《National Science Review》 (国家科学评论(英文版))

年 卷 期：2024年第06期

页      面：285-293页

核心收录：

学科分类：0710[理学-生物学] 07[理学] 08[工学] 070205[理学-凝聚态物理] 09[农学] 080501[工学-材料物理与化学] 071007[理学-遗传学] 0805[工学-材料科学与工程（可授工学、理学学位）] 0901[农学-作物学] 0836[工学-生物工程] 090102[农学-作物遗传育种] 0702[理学-物理学] 

基　　金：supported by the National Key R&D Program of China (2019YFA0802801, 2018YFA0801401 and2022YFF1002801) the Key R&D Program of Hubei Province(2022BCA089 to H.Y. and 2022ACA005 to Y.Z.) the Ministry of Agriculture and Rural Affairs of China the National Natural Science Foundation of China (31871345 and 32071442 to H.Y.,31972936 to Y.Z.) the State Key Laboratory for Animal Disease Control and Prevention (SKLVBF202202) the Medical Science Advancement Program (Basic Medical Sciences) of Wuhan University (TFJC2018004) the Fundamental Research Funds for the Central Universities (2042022dx0003 and 2042022kf1190) the Applied Basic Frontier Program of Wuhan City (2020020601012216 to H.Y.) the startup funding from Wuhan University (to H.Y. and Y.Z.) 

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 HTO12 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 HTO12 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.