靶向 NLRP3 炎性小体的基因编辑治疗炎症性疾病。
Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases.
机构信息
Guangzhou First People's Hospital, School of Medicine, South China University of Technology, 510006, Guangzhou, Guangdong, China.
National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, 510006, Guangzhou, Guangdong, China.
出版信息
Nat Commun. 2018 Oct 5;9(1):4092. doi: 10.1038/s41467-018-06522-5.
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) (CLAN), we disrupt NLRP3 of macrophages, inhibiting the activation of the NLRP3 inflammasome in response to diverse stimuli. After intravenous injection, CLAN mitigates acute inflammation of LPS-induced septic shock and monosodium urate crystal (MSU)-induced peritonitis. In addition, CLAN 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.
NLRP3 炎性小体是治疗多种炎症性疾病的研究热点，但如何促进现有治疗方法的发展仍然是一个巨大的挑战。CRISPR/Cas9 作为一种基因编辑工具，可以在基因组水平上直接靶向 NLRP3 进行基因敲除。在本研究中，我们筛选了一种优化的阳离子脂质体辅助纳米颗粒（CLAN），以将 Cas9 mRNA（mCas9）和靶向 NLRP3 的指导 RNA（gRNA）递送至巨噬细胞。通过使用封装 mCas9 和靶向 NLRP3 的 gRNA（gNLRP3）的 CLAN（CLAN），我们破坏了巨噬细胞中的 NLRP3，抑制了其对各种刺激的反应性激活。静脉注射后，CLAN 减轻了 LPS 诱导的脓毒症休克和单钠尿酸盐晶体（MSU）诱导的腹膜炎的急性炎症。此外，CLAN 治疗改善了高脂肪饮食（HFD）诱导的 2 型糖尿病（T2D）患者的胰岛素敏感性并减少了脂肪组织炎症。因此，我们的研究为治疗 NLRP3 依赖性炎症性疾病提供了一种有前途的策略，并为将 CRISPR/Cas9 递送至巨噬细胞提供了一种载体。
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