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Generation of Cationic Nanoliposomes for the Efficient Delivery of In Vitro Transcribed Messenger RNA
Published on: February 1, 2019
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High-throughput synthesis and optimization of ionizable lipids through A3 coupling for efficient mRNA delivery
Jingjiao Li1,2, Jie Hu3, Danni Jin4
1Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
Journal of Nanobiotechnology
|November 4, 2024
Summary
Optimizing ionizable lipids (ILs) for lipid nanoparticles (LNPs) enhances mRNA delivery. Specific structural features like 18-carbon chains and alkynes converted to alkanes significantly improve LNP efficacy for mRNA vaccines and therapies.
Area of Science:
- Biotechnology
- Drug Delivery
- Molecular Biology
Background:
- Lipid nanoparticles (LNPs) are essential carriers for mRNA delivery in vaccines and therapies.
- The efficacy of mRNA delivery is critically dependent on the chemical structure of ionizable lipids (ILs) within LNPs.
Purpose of the Study:
- To investigate the structure-function relationships of alkyne-bearing ionizable lipids (ILs) for mRNA delivery.
- To identify optimal structural features of ILs for enhanced LNP-mediated mRNA delivery.
Main Methods:
- Synthesis of 623 alkyne-bearing ILs using A³ coupling reaction.
- Assessment of ILs' mRNA delivery efficiency in vitro and in vivo.
- Evaluation of structural variations (chain length, saturation, double bond placement, alkyne position) and modifications (alkyne to alkane conversion).
Main Results:
- ILs with 18-carbon alkyl chains, a cis-double bond, and ethanolamine head groups showed superior mRNA delivery.
- Alkynes near nitrogen atoms reduced LNP pKa and hindered delivery; conversion to alkanes significantly improved efficacy.
- Optimized ILs combined with cKK-E12 demonstrated synergistic LNPs with augmented in vivo mRNA expression.
Conclusions:
- Established structure-function relationships for ILs in LNP-based mRNA delivery.
- Provided a foundation for the rational design of novel ILs to improve LNP efficacy for mRNA applications.
