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Freezing induced incorporation of betaine in lipid nanoparticles enhances mRNA delivery

Author

Listed:
  • Xingdi Cheng

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xia Zheng

    (University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Kun Tao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Haonan Huo

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Zhang Liu

    (Chinese Academy of Sciences)

  • Xueguang Lu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jianjun Wang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

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.

Suggested Citation

  • Xingdi Cheng & Xia Zheng & Kun Tao & Haonan Huo & Zhang Liu & Xueguang Lu & Jianjun Wang, 2025. "Freezing induced incorporation of betaine in lipid nanoparticles enhances mRNA delivery," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60040-9
    DOI: 10.1038/s41467-025-60040-9
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