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

被引:164
作者
Xu, Congfei [1 ,2 ,3 ]
Lu, Zidong [1 ,2 ]
Luo, Yingli [4 ]
Liu, Yang [4 ]
Cao, Zhiting [4 ]
Shen, Song [1 ,2 ,3 ]
Li, Hongjun [1 ,2 ,3 ]
Liu, Jing [4 ]
Chen, Kaige [4 ]
Chen, Zhiyao [4 ]
Yang, Xianzhu [1 ,2 ,3 ]
Gu, Zhen [5 ]
Wang, Jun [1 ,2 ,3 ,6 ]
机构
[1] South China Univ Technol, Sch Med, Guangzhou Peoples Hosp 1, Guangzhou 510006, Guangdong, Peoples R China
[2] South China Univ Technol, Natl Engn Res Ctr Tissue Restorat & Reconstruct, Guangzhou 510006, Guangdong, Peoples R China
[3] South China Univ Technol, Sch Biomed Sci & Engn, Minist Educ, Key Lab Biomed Mat & Engn, Guangzhou Int Campus, Guangzhou 510006, Guangdong, Peoples R China
[4] Univ Sci & Technol China, Sch Life Sci, Hefei 230027, Anhui, Peoples R China
[5] Univ Calif Los Angeles, Dept Bioengn, Calif Nanosyst Inst, Los Angeles, CA 90095 USA
[6] South China Univ Technol, Key Lab Biomed Engn Guangdong Prov, Guangzhou 510006, Guangdong, Peoples R China
来源
NATURE COMMUNICATIONS | 2018年 / 9卷
基金
国家重点研发计划; 中国博士后科学基金; 中国国家自然科学基金;
关键词
DUCHENNE MUSCULAR-DYSTROPHY; CAS9; MESSENGER-RNA; IN-VIVO; CRISPR-CAS9; SYSTEM; NONVIRAL DELIVERY; MOUSE MODEL; NANOPARTICLES; CRISPR/CAS9; ACTIVATION; DNA;
D O I
10.1038/s41467-018-06522-5
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页数:14
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