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Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases

Author

Listed:
  • Congfei Xu

    (South China University of Technology
    South China University of Technology
    South China University of Technology, Guangzhou International Campus)

  • Zidong Lu

    (South China University of Technology
    South China University of Technology)

  • Yingli Luo

    (School of Life Sciences, University of Science and Technology of China)

  • Yang Liu

    (School of Life Sciences, University of Science and Technology of China)

  • Zhiting Cao

    (School of Life Sciences, University of Science and Technology of China)

  • Song Shen

    (South China University of Technology
    South China University of Technology
    South China University of Technology, Guangzhou International Campus)

  • Hongjun Li

    (South China University of Technology
    South China University of Technology
    South China University of Technology, Guangzhou International Campus)

  • Jing Liu

    (School of Life Sciences, University of Science and Technology of China)

  • Kaige Chen

    (School of Life Sciences, University of Science and Technology of China)

  • Zhiyao Chen

    (School of Life Sciences, University of Science and Technology of China)

  • Xianzhu Yang

    (South China University of Technology
    South China University of Technology
    South China University of Technology, Guangzhou International Campus)

  • Zhen Gu

    (University of California)

  • Jun Wang

    (South China University of Technology
    South China University of Technology
    South China University of Technology, Guangzhou International Campus
    South China University of Technology)

Abstract

The NLRP3 inflammasome is a well-studied target for the treatment of multiple inflammatory diseases, but how to promote the current therapeutics remains a large challenge. CRISPR/Cas9, as a gene editing tool, allows for direct ablation of NLRP3 at the genomic level. In this study, we screen an optimized cationic lipid-assisted nanoparticle (CLAN) to deliver Cas9 mRNA (mCas9) and guide RNA (gRNA) into macrophages. By using CLAN encapsulating mCas9 and gRNA-targeting NLRP3 (gNLRP3) (CLANmCas9/gNLRP3), we disrupt NLRP3 of macrophages, inhibiting the activation of the NLRP3 inflammasome in response to diverse stimuli. After intravenous injection, CLANmCas9/gNLRP3 mitigates acute inflammation of LPS-induced septic shock and monosodium urate crystal (MSU)-induced peritonitis. In addition, CLANmCas9/gNLRP3 treatment improves insulin sensitivity and reduces adipose inflammation of high-fat-diet (HFD)-induced type 2 diabetes (T2D). Thus, our study provides a promising strategy for treating NLRP3-dependent inflammatory diseases and provides a carrier for delivering CRISPR/Cas9 into macrophages.

Suggested Citation

  • Congfei Xu & Zidong Lu & Yingli Luo & Yang Liu & Zhiting Cao & Song Shen & Hongjun Li & Jing Liu & Kaige Chen & Zhiyao Chen & Xianzhu Yang & Zhen Gu & Jun Wang, 2018. "Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06522-5
    DOI: 10.1038/s41467-018-06522-5
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