Freezing induced incorporation of betaine in lipid nanoparticles enhances mRNA delivery

Xingdi Cheng, Xia Zheng, Kun Tao, Haonan Huo, Zhang Liu (), Xueguang Lu () and Jianjun Wang ()
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Xingdi Cheng: Chinese Academy of Sciences
Xia Zheng: University of Chinese Academy of Sciences
Kun Tao: Chinese Academy of Sciences
Haonan Huo: Chinese Academy of Sciences
Zhang Liu: Chinese Academy of Sciences
Xueguang Lu: Chinese Academy of Sciences
Jianjun Wang: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Lipid nanoparticles (LNPs) are key non-viral carriers for mRNA vaccines and therapeutics, but the inherent instability of mRNA necessitates sub-zero storage with cryoprotectants (CPAs) to prevent freeze-induced LNP aggregation and compromised mRNA delivery. Here we show that ice formation during freezing concentrates CPAs with LNPs in the remaining liquid—a phenomenon known as freeze concentration. This creates a steep concentration gradient of CPAs across the lipid membrane that drives passive CPAs diffusion into LNPs. By leveraging this process, we developed betaine-based CPAs that both preserve the stability of LNP and enter LNP during freeze-thaw. The incorporated betaine enhances endosomal escape and boosts mRNA delivery of LNP. In female mice, betaine-loaded LNPs elicit stronger humoral and cellular immune responses, providing dose-sparing advantages. These findings highlight freeze concentration as a promising LNP formulation strategy and underscore the role of CPA as active modulators of LNP structure and function.

Date: 2025
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DOI: 10.1038/s41467-025-60040-9

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