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

Congfei Xu, Zidong Lu, Yingli Luo, Yang Liu, Zhiting Cao, Song Shen, Hongjun Li, Jing Liu, Kaige Chen, Zhiyao Chen, Xianzhu Yang, Zhen Gu and Jun Wang ()
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Congfei Xu: South China University of Technology
Zidong Lu: 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
Hongjun Li: South China University of Technology
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
Zhen Gu: University of California
Jun Wang: South China University of Technology

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06522-5

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