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Ligand-tethered lipid nanoparticles for targeted RNA delivery to treat liver fibrosis

Author

Listed:
  • Xuexiang Han

    (University of Pennsylvania)

  • Ningqiang Gong

    (University of Pennsylvania)

  • Lulu Xue

    (University of Pennsylvania)

  • Margaret M. Billingsley

    (University of Pennsylvania)

  • Rakan El-Mayta

    (University of Pennsylvania)

  • Sarah J. Shepherd

    (University of Pennsylvania)

  • Mohamad-Gabriel Alameh

    (University of Pennsylvania
    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

Lipid nanoparticle-mediated RNA delivery holds great potential to treat various liver diseases. However, targeted delivery of RNA therapeutics to activated liver-resident fibroblasts for liver fibrosis treatment remains challenging. Here, we develop a combinatorial library of anisamide ligand-tethered lipidoids (AA-lipidoids) using a one-pot, two-step modular synthetic method and adopt a two-round screening strategy to identify AA-lipidoids with both high potency and selectivity to deliver RNA payloads to activated fibroblasts. The lead AA-lipidoid AA-T3A-C12 mediates greater RNA delivery and transfection of activated fibroblasts than its analog without anisamide and the FDA-approved MC3 ionizable lipid. In a preclinical model of liver fibrosis, AA-T3A-C12 enables ~65% silencing of heat shock protein 47, a therapeutic target primarily expressed by activated fibroblasts, which is 2-fold more potent than MC3, leading to significantly reduced collagen deposition and liver fibrosis. These results demonstrate the potential of AA-lipidoids for targeted RNA delivery to activated fibroblasts. Furthermore, these synthetic methods and screening strategies open a new avenue to develop and discover potent lipidoids with targeting properties, which can potentially enable RNA delivery to a range of cell and tissue types that are challenging to access using traditional lipid nanoparticle formulations.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35637-z
    DOI: 10.1038/s41467-022-35637-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. 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.
    3. Xuexiang Han & Yiye Li & Ying Xu & Xiao Zhao & Yinlong Zhang & Xiao Yang & Yongwei Wang & Ruifang Zhao & Gregory J. Anderson & Yuliang Zhao & Guangjun Nie, 2018. "Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem," Nature Communications, Nature, vol. 9(1), pages 1-18, December.
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    Cited by:

    1. 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.

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