2. Academic Validation
  3. Minimizing the ratio of ionizable lipid in lipid nanoparticles for in vivo base editing

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

  • Natl Sci Rev. 2024 Apr 3;11(6):nwae135. doi: 10.1093/nsr/nwae135.
Qiubing Chen 1 2,  Xuebin Wang 1 2,  Yizhou Zhang 1 2,  Ming Tian 1 2,  Junyi Duan 1 2,  Ying Zhang 1 3,  Hao Yin 1 2 4 5
Affiliations

Affiliations

  • 1 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.
  • 2 State Key Laboratory of Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan 430071, China.
  • 3 Department of Rheumatology and Immunology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
  • 4 Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan 430071, China.
  • 5 RNA Institute, Wuhan University, Wuhan 430071, China.
PMID: 38770531 DOI: 10.1093/nsr/nwae135
Abstract

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.

Keywords

Pcsk9; base editor delivery; ionizable lipid; lipid nanoparticle; mRNA delivery.

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