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In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors

Author

Listed:
  • Xuexiang Han

    (University of Pennsylvania
    University of Chinese Academy of Sciences)

  • Junchao Xu

    (University of Pennsylvania)

  • Ying Xu

    (Case Western Reserve University)

  • Mohamad-Gabriel Alameh

    (University of Pennsylvania
    University of Pennsylvania)

  • Lulu Xue

    (University of Pennsylvania)

  • Ningqiang Gong

    (University of Pennsylvania)

  • Rakan El-Mayta

    (University of Pennsylvania)

  • Rohan Palanki

    (University of Pennsylvania)

  • Claude C. Warzecha

    (University of Pennsylvania)

  • Gan Zhao

    (University of Pennsylvania)

  • Andrew E. Vaughan

    (University of Pennsylvania)

  • James M. Wilson

    (University of Pennsylvania)

  • Drew Weissman

    (University of Pennsylvania
    University of Pennsylvania)

  • Michael J. Mitchell

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

Abstract

The ionizable lipidoid is a key component of lipid nanoparticles (LNPs). Degradable lipidoids containing extended alkyl branches have received tremendous attention, yet their optimization and investigation are underappreciated. Here, we devise an in situ construction method for the combinatorial synthesis of degradable branched (DB) lipidoids. We find that appending branch tails to inefficacious lipidoids via degradable linkers boosts mRNA delivery efficiency up to three orders of magnitude. Combinatorial screening and systematic investigation of two libraries of DB-lipidoids reveal important structural criteria that govern their in vivo potency. The lead DB-LNP demonstrates robust delivery of mRNA therapeutics and gene editors into the liver. In a diet-induced obese mouse model, we show that repeated administration of DB-LNP encapsulating mRNA encoding human fibroblast growth factor 21 alleviates obesity and fatty liver. Together, we offer a construction strategy for high-throughput and cost-efficient synthesis of DB-lipidoids. This study provides insights into branched lipidoids for efficient mRNA delivery.

Suggested Citation

  • Xuexiang Han & Junchao Xu & Ying Xu & Mohamad-Gabriel Alameh & Lulu Xue & Ningqiang Gong & Rakan El-Mayta & Rohan Palanki & Claude C. Warzecha & Gan Zhao & Andrew E. Vaughan & James M. Wilson & Drew W, 2024. "In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45537-z
    DOI: 10.1038/s41467-024-45537-z
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    References listed on IDEAS

    as
    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.
    2. Xuexiang Han & Ningqiang Gong & Lulu Xue & Margaret M. Billingsley & Rakan El-Mayta & Sarah J. Shepherd & Mohamad-Gabriel Alameh & Drew Weissman & Michael J. Mitchell, 2023. "Ligand-tethered lipid nanoparticles for targeted RNA delivery to treat liver fibrosis," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Kathryn A. Whitehead & J. Robert Dorkin & Arturo J. Vegas & Philip H. Chang & Omid Veiseh & Jonathan Matthews & Owen S. Fenton & Yunlong Zhang & Karsten T. Olejnik & Volkan Yesilyurt & Delai Chen & Sc, 2014. "Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity," Nature Communications, Nature, vol. 5(1), pages 1-10, September.
    4. Eriya Kenjo & Hiroyuki Hozumi & Yukimasa Makita & Kumiko A. Iwabuchi & Naoko Fujimoto & Satoru Matsumoto & Maya Kimura & Yuichiro Amano & Masataka Ifuku & Youichi Naoe & Naoto Inukai & Akitsu Hotta, 2021. "Low immunogenicity of LNP allows repeated administrations of CRISPR-Cas9 mRNA into skeletal muscle in mice," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    5. Lei Miao & Jiaqi Lin & Yuxuan Huang & Linxian Li & Derfogail Delcassian & Yifan Ge & Yunhua Shi & Daniel G. Anderson, 2020. "Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
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