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Structure-guided design of endosomolytic chloroquine-like lipid nanoparticles for mRNA delivery and genome editing

Author

Listed:
  • Zhen Liu

    (Jinan University)

  • Jiacai Wu

    (Southern University of Science and Technology)

  • Ning Wang

    (Southern University of Science and Technology)

  • Yongqi Lin

    (Southern University of Science and Technology)

  • Ruiteng Song

    (Jinan University)

  • Min Zhang

    (Jinan University)

  • Bin Li

    (Jinan University
    Southern University of Science and Technology)

Abstract

Despite remarkable progress in designing RNA delivery systems, endosomal escape remains a recognized challenge for efficient RNA delivery. In this study, we develop a robust mRNA delivery platform termed endosomolytic chloroquine-like optimized lipid nanoparticles (ecoLNPs) for versatile mRNA delivery in vitro and in vivo via integrating the signature scaffold extracted from endosomolytic chloroquine into ionizable lipids. RNase-resistant ecoLNPs are capable of delivering a broad variety of mRNA payloads to diverse cell types, even hard-to-transfect 3D cells, with an efficiency of up to 18.9-fold higher than that of commercial transfection reagents. The pH-responsive endosomolytic activity of ecoLNPs can be largely attributed to the proton sponge effect and saposin B-promoted membrane disruption. In vivo, ecoLNPs enable potent local and systemic mRNA delivery and exhibit comparable potency to the clinically approved mRNA vaccine carrier, but strong tropism for lymph nodes following intramuscular injection. Furthermore, ecoLNPs are able to retain in vivo delivery potency for at least one week under non-frozen conditions and induce efficient genome editing in transgenic mice. Overall, the structure-guided integration strategy provides a pathway for de novo design of endosomolytic mRNA delivery systems.

Suggested Citation

  • Zhen Liu & Jiacai Wu & Ning Wang & Yongqi Lin & Ruiteng Song & Min Zhang & Bin Li, 2025. "Structure-guided design of endosomolytic chloroquine-like lipid nanoparticles for mRNA delivery and genome editing," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59501-y
    DOI: 10.1038/s41467-025-59501-y
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    References listed on IDEAS

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    1. Xuexiang Han & Hanwen Zhang & Kamila Butowska & Kelsey L. Swingle & Mohamad-Gabriel Alameh & Drew Weissman & Michael J. Mitchell, 2021. "An ionizable lipid toolbox for RNA delivery," Nature Communications, Nature, vol. 12(1), pages 1-6, December.
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