A fluorinated ionizable lipid improves the mRNA delivery efficiency of lipid nanoparticles

May 2, 2023Journal of materials chemistry. B

A fluorinated lipid helps lipid nanoparticles deliver mRNA more efficiently

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Abstract

Hybrid lipid nanoparticles (hybrid-LNPs) significantly enhance mRNA delivery efficiency compared to traditional lipid nanoparticles.

Lipid nanoparticles are critical for delivering mRNA into cells.
A new ionizable lipid with fluorinated alkyl chains (F-L319) was synthesized.
F-L319 alone resulted in decreased mRNA encapsulation and delivery efficiency compared to its hydrocarbon counterpart (L319).
Combining F-L319 and L319 in hybrid-LNPs improved mRNA delivery efficiency.
Intravenous injection of hybrid-LNPs led to targeted mRNA expression in the spleen.
The enhanced delivery efficiency of hybrid-LNPs is linked to better mRNA encapsulation and cellular uptake.

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The efficacy of messenger RNA (mRNA)-based vaccines or therapies relies on delivery vehicles that can transport them into the cytosol of cells. Lipid nanoparticles (LNPs) are the most clinically advanced carrier for mRNA. The chemical structure of an ionizable lipid is critical for the delivery efficiency of the LNPs. Herein, we synthesize a new ionizable lipid containing fluorinated alkyl chains (F-L319) and evaluate its mRNA delivery efficiency compared to its hydrocarbon counterpart (L319). While LNPs formulated with F-L319 alone showed decreased mRNA encapsulation and delivery efficiencies in comparison to the L319-LNP, we found that combining the appropriate ratios of F-L319 and L319 as hybrid ionizable lipids in LNPs (hybrid-LNPs) greatly enhanced mRNA delivery efficiency bothand. Upon intravenous injection, the hybrid-LNP showed targeted mRNA expression in the spleen. Mechanistic studies indicate that the enhanced mRNA delivery of the hybrid-LNP is attributed to both improved mRNA encapsulation and cellular uptake. Collectively, fluorination of ionizable lipids represents a promising strategy to improve the delivery efficiency of LNPs. in vitro in vivo

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A fluorinated ionizable lipid improves the mRNA delivery efficiency of lipid nanoparticles

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