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Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity

Author

Listed:
  • Kathryn A. Whitehead

    (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
    Present address: Department of Chemical Engineering, Carnegie Mellon University, 5000 Forbes Avenue, Pittsburgh, Pennsylvania 15217, USA)

  • J. Robert Dorkin

    (Massachusetts Institute of Technology)

  • Arturo J. Vegas

    (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology)

  • Philip H. Chang

    (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology)

  • Omid Veiseh

    (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology)

  • Jonathan Matthews

    (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology)

  • Owen S. Fenton

    (Massachusetts Institute of Technology)

  • Yunlong Zhang

    (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology)

  • Karsten T. Olejnik

    (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology)

  • Volkan Yesilyurt

    (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology)

  • Delai Chen

    (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology)

  • Scott Barros

    (Alnylam Pharmaceuticals)

  • Boris Klebanov

    (Alnylam Pharmaceuticals)

  • Tatiana Novobrantseva

    (Alnylam Pharmaceuticals)

  • Robert Langer

    (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    The Institute for Medical Engineering and Science, Massachusetts Institute of Technology)

  • Daniel G. Anderson

    (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    The Institute for Medical Engineering and Science, Massachusetts Institute of Technology)

Abstract

One of the most significant challenges in the development of clinically viable delivery systems for RNA interference therapeutics is to understand how molecular structures influence delivery efficacy. Here, we have synthesized 1,400 degradable lipidoids and evaluate their transfection ability and structure–function activity. We show that lipidoid nanoparticles mediate potent gene knockdown in hepatocytes and immune cell populations on IV administration to mice (siRNA EC50 values as low as 0.01 mg kg−1). We identify four necessary and sufficient structural and pKa criteria that robustly predict the ability of nanoparticles to mediate greater than 95% protein silencing in vivo. Because these efficacy criteria can be dictated through chemical design, this discovery could eliminate our dependence on time-consuming and expensive cell culture assays and animal testing. Herein, we identify promising degradable lipidoids and describe new design criteria that reliably predict in vivo siRNA delivery efficacy without any prior biological testing.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5277
    DOI: 10.1038/ncomms5277
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    Citations

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    Cited by:

    1. 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.
    2. 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.
    3. 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.
    4. Mengjie Zhang & Abid Hussain & Bo Hu & Haiyin Yang & Chunhui Li & Shuai Guo & Xiaofeng Han & Bei Li & Yunlu Dai & Yuhong Cao & Hang Chi & Yuhua Weng & Cheng-Feng Qin & Yuanyu Huang, 2024. "Atavistic strategy for the treatment of hyperuricemia via ionizable liposomal mRNA," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Roy Pattipeiluhu & Ye Zeng & Marco M.R.M. Hendrix & Ilja K. Voets & Alexander Kros & Thomas H. Sharp, 2024. "Liquid crystalline inverted lipid phases encapsulating siRNA enhance lipid nanoparticle mediated transfection," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. Yue Xu & Shihao Ma & Haotian Cui & Jingan Chen & Shufen Xu & Fanglin Gong & Alex Golubovic & Muye Zhou & Kevin Chang Wang & Andrew Varley & Rick Xing Ze Lu & Bo Wang & Bowen Li, 2024. "AGILE platform: a deep learning powered approach to accelerate LNP development for mRNA delivery," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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