Citation: Haoran Xu, Jiaqi Fan, Jiwei Liu, Qi Wei, Ruoshui Li, Pengcheng Yuan, Bing Xiao, Ying Piao, Wenjing Sun, Jiajia Xiang, Shiqun Shao, Zhuxian Zhou, Youqing Shen, Nigel K.H. Slater, Jianbin Tang. Tetra-branched ionizable lipids enhance the stability and transfection efficiency of lipid nanoparticles for mRNA delivery[J]. Chinese Chemical Letters, ;2025, 36(11): 110833. doi: 10.1016/j.cclet.2025.110833 shu

Tetra-branched ionizable lipids enhance the stability and transfection efficiency of lipid nanoparticles for mRNA delivery

Haoran Xu ^a ,
Jiaqi Fan ^a ,
Jiwei Liu ^a ,
Qi Wei ^a ,
Ruoshui Li ^a ,
Pengcheng Yuan ^a ,
Bing Xiao ^a ,
Ying Piao ^a ,
Wenjing Sun ^b ,
Jiajia Xiang ^a ,
Shiqun Shao ^{a, b} ,
Zhuxian Zhou ^a ,
Youqing Shen ^a ,
Nigel K.H. Slater ^a ,
Jianbin Tang ^{a, b, *,}

a.
Zhejiang Key Laboratory of Smart Biomaterials, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
b.
ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311215, China

jianbin@zju.edu.cn

Received Date: 30 October 2024
Revised Date: 31 December 2024
Accepted Date: 6 January 2025
Available Online: 7 January 2025

Figures(4)

mRNA is a highly promising approach for disease prevention, yet its further application is currently limited by the low efficiency of delivery. Lipid nanoparticles (LNPs) are the mainstream delivery vehicles at present, and ionizable lipids, as a key component, have a particularly significant impact on delivery efficiency. To improve the efficiency of delivery, a library of ionizable lipids with tetra-branched hydrophobic tails was designed and synthesized by the Michael addition reaction. From this library, the lipid 10A was selected for the highest delivery efficiency. Further formulation screening yielded LNPs with excellent performance, which showed good efficacy in tumor prevention experiments. At the same time, the structure-activity relationship between the ionizable lipid structure and the delivery efficiency was elucidated. It was that the tetra-branched hydrophobic tails, as compared with the di-branched hydrophobic tails enhanced the stability of LNPs, provided uniformity of particle size and improved the efficiency of endocytosis and lysosomal escape, resulting in higher delivery efficiency. Meanwhile, tetra-branched lipids with hydroxyl groups in the head group performed even better. This research provides a theoretical basis and foundation for guiding the development of the next generation of ionizable lipids, and the developed 10A LNP also shows broad prospects for clinical translation.
- mRNA vaccine,
- Lipid nanoparticles,
- Tetra-branched lipids,
- Structure-activity relationship,
- mRNA delivery
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