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Charge-assisted stabilization of lipid nanoparticles enables inhaled mRNA delivery for mucosal vaccination

Author

Listed:
  • Shuai Liu

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

  • Yixing Wen

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

  • Xinzhu Shan

    (Peking University
    Peking University)

  • Xinghuan Ma

    (Dalian University of Technology)

  • Chen Yang

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

  • Xingdi Cheng

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

  • Yuanyuan Zhao

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

  • Jingjiao Li

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

  • Shiwei Mi

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

  • Haonan Huo

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

  • Wei Li

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

  • Ziqiong Jiang

    (Peking University
    Peking University)

  • Yijia Li

    (Peking University
    Peking University)

  • Jiaqi Lin

    (Dalian University of Technology)

  • Lei Miao

    (Peking University
    Peking University)

  • Xueguang Lu

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

Abstract

Inhaled delivery of messenger RNA (mRNA) using lipid nanoparticle (LNP) holds immense promise for treating pulmonary diseases or serving as a mucosal vaccine. However, the unsatisfactory delivery efficacy caused by the disintegration and aggregation of LNP during nebulization represents a major obstacle. To address this, we develop a charge-assisted stabilization (CAS) strategy aimed at inducing electrostatic repulsions among LNPs to enhance their colloidal stability. By optimizing the surface charges using a peptide-lipid conjugate, the leading CAS-LNP demonstrates exceptional stability during nebulization, resulting in efficient pulmonary mRNA delivery in mouse, dog, and pig. Inhaled CAS-LNP primarily transfect dendritic cells, triggering robust mucosal and systemic immune responses. We demonstrate the efficacy of inhaled CAS-LNP as a vaccine for SARS-CoV-2 Omicron variant and as a cancer vaccine to inhibit lung metastasis. Our findings illustrate the design principles of nebulized LNPs, paving the way of developing inhaled mRNA vaccines and therapeutics.

Suggested Citation

  • Shuai Liu & Yixing Wen & Xinzhu Shan & Xinghuan Ma & Chen Yang & Xingdi Cheng & Yuanyuan Zhao & Jingjiao Li & Shiwei Mi & Haonan Huo & Wei Li & Ziqiong Jiang & Yijia Li & Jiaqi Lin & Lei Miao & Xuegua, 2024. "Charge-assisted stabilization of lipid nanoparticles enables inhaled mRNA delivery for mucosal vaccination," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53914-x
    DOI: 10.1038/s41467-024-53914-x
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    References listed on IDEAS

    as
    1. Tuo Wei & Yehui Sun & Qiang Cheng & Sumanta Chatterjee & Zachary Traylor & Lindsay T. Johnson & Melissa L. Coquelin & Jialu Wang & Michael J. Torres & Xizhen Lian & Xu Wang & Yufen Xiao & Craig A. Hod, 2023. "Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
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