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Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing

Author

Listed:
  • Tuo Wei

    (Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center)

  • Qiang Cheng

    (Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center)

  • Yi-Li Min

    (Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center
    Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, The University of Texas Southwestern Medical Center)

  • Eric N. Olson

    (Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center
    Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, The University of Texas Southwestern Medical Center)

  • Daniel J. Siegwart

    (Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center)

Abstract

CRISPR-Cas9 has emerged as a powerful technology that relies on Cas9/sgRNA ribonucleoprotein complexes (RNPs) to target and edit DNA. However, many therapeutic targets cannot currently be accessed due to the lack of carriers that can deliver RNPs systemically. Here, we report a generalizable methodology that allows engineering of modified lipid nanoparticles to efficiently deliver RNPs into cells and edit tissues including muscle, brain, liver, and lungs. Intravenous injection facilitated tissue-specific, multiplexed editing of six genes in mouse lungs. High carrier potency was leveraged to create organ-specific cancer models in livers and lungs of mice though facile knockout of multiple genes. The developed carriers were also able to deliver RNPs to restore dystrophin expression in DMD mice and significantly decrease serum PCSK9 level in C57BL/6 mice. Application of this generalizable strategy will facilitate broad nanoparticle development for a variety of disease targets amenable to protein delivery and precise gene correction approaches.

Suggested Citation

  • Tuo Wei & Qiang Cheng & Yi-Li Min & Eric N. Olson & Daniel J. Siegwart, 2020. "Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17029-3
    DOI: 10.1038/s41467-020-17029-3
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    Cited by:

    1. Tuo Wei & Yehui Sun & Qiang Cheng & Sumanta Chatterjee & Zachary Traylor & Lindsay T. Johnson & Melissa L. Coquelin & Jialu Wang & Michael J. Torres & Xizhen Lian & Xu Wang & Yufen Xiao & Craig A. Hod, 2023. "Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Yining Zhu & Ruochen Shen & Ivan Vuong & Rebekah A. Reynolds & Melanie J. Shears & Zhi-Cheng Yao & Yizong Hu & Won June Cho & Jiayuan Kong & Sashank K. Reddy & Sean C. Murphy & Hai-Quan Mao, 2022. "Multi-step screening of DNA/lipid nanoparticles and co-delivery with siRNA to enhance and prolong gene expression," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Milan Gautam & Antony Jozic & Grace Li-Na Su & Marco Herrera-Barrera & Allison Curtis & Sebastian Arrizabalaga & Wayne Tschetter & Renee C. Ryals & Gaurav Sahay, 2023. "Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    4. Mohamed Fareh & Wei Zhao & Wenxin Hu & Joshua M. L. Casan & Amit Kumar & Jori Symons & Jennifer M. Zerbato & Danielle Fong & Ilia Voskoboinik & Paul G. Ekert & Rajeev Rudraraju & Damian F. J. Purcell , 2021. "Reprogrammed CRISPR-Cas13b suppresses SARS-CoV-2 replication and circumvents its mutational escape through mismatch tolerance," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

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