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Reformulating lipid nanoparticles for organ-targeted mRNA accumulation and translation

Author

Listed:
  • Kexin Su

    (Zhejiang University)

  • Lu Shi

    (Zhejiang University
    Zhejiang University)

  • Tao Sheng

    (Zhejiang University)

  • Xinxin Yan

    (Zhejiang University)

  • Lixin Lin

    (Zhejiang University)

  • Chaoyang Meng

    (Zhejiang University)

  • Shiqi Wu

    (Zhejiang University
    Zhejiang University)

  • Yuxuan Chen

    (Zhejiang University)

  • Yao Zhang

    (Zhejiang University)

  • Chaorong Wang

    (Zhejiang University)

  • Zichuan Wang

    (Zhejiang University)

  • Junjie Qiu

    (Zhejiang University)

  • Jiahui Zhao

    (Zhejiang University)

  • Tengfei Xu

    (Zhejiang University)

  • Yuan Ping

    (Zhejiang University
    Zhejiang University)

  • Zhen Gu

    (Zhejiang University
    Zhejiang University)

  • Shuai Liu

    (Zhejiang University
    Zhejiang University
    Zhejiang University)

Abstract

Fully targeted mRNA therapeutics necessitate simultaneous organ-specific accumulation and effective translation. Despite some progress, delivery systems are still unable to fully achieve this. Here, we reformulate lipid nanoparticles (LNPs) through adjustments in lipid material structures and compositions to systematically achieve the pulmonary and hepatic (respectively) targeted mRNA distribution and expression. A combinatorial library of degradable-core based ionizable cationic lipids is designed, following by optimisation of LNP compositions. Contrary to current LNP paradigms, our findings demonstrate that cholesterol and phospholipid are dispensable for LNP functionality. Specifically, cholesterol-removal addresses the persistent challenge of preventing nanoparticle accumulation in hepatic tissues. By modulating and simplifying intrinsic LNP components, concurrent mRNA accumulation and translation is achieved in the lung and liver, respectively. This targeting strategy is applicable to existing LNP systems with potential to expand the progress of precise mRNA therapy for diverse diseases.

Suggested Citation

  • Kexin Su & Lu Shi & Tao Sheng & Xinxin Yan & Lixin Lin & Chaoyang Meng & Shiqi Wu & Yuxuan Chen & Yao Zhang & Chaorong Wang & Zichuan Wang & Junjie Qiu & Jiahui Zhao & Tengfei Xu & Yuan Ping & Zhen Gu, 2024. "Reformulating lipid nanoparticles for organ-targeted mRNA accumulation and translation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50093-7
    DOI: 10.1038/s41467-024-50093-7
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    References listed on IDEAS

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