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

Xu, Cong; Lu, Zi-Dong; Luo, Ying-Li; Liu, Yang; Cao, Zhi-Ting; Shen, Song; Li, Hongjun; Liu, Jing; Chen, Kaige; Chen, Zhiyao; Yang, Xianzhu; Gu, Zhen; Wang, Jun

doi:10.1038/s41467-018-06522-5

Cited by 145 publications

(92 citation statements)

References 63 publications

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“…To evaluate the siRNA delivery efficiency and therapeutic efficacy of the cNC, we focus on the treatment of obesityinduced insulin resistance by silencing inflammation-related gene expression [27,28]. Conventional anti-diabetes drugs, such as insulin, are often associated with weight gain [29], since insulin stimulates lipid storage in peripheral adipose tissues [30].…”

Section: Introductionmentioning

confidence: 99%

Collaborative assembly-mediated siRNA delivery for relieving inflammation-induced insulin resistance

Shen

Zhang

et al. 2020

Nano Res.

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Obesity plays a primary causative role in insulin resistance and hyperglycemia that contributes to type 2 diabetes. Excess lipid storage in the liver renders activation of the resident macrophages and chronic secretion of inflammatory mediators, therefore causing or aggravating insulin resistance. Herein, we develop collaborative assemblies using a "one-pot" synthesis method for macrophage-specific delivery of small interfering RNAs (siRNAs) that target the inflammatory proteins. Ternary nanocomplex (NC) composed of the siRNA molecule, a synthetic thiol-bearing methacrylated hyaluronic acid (sm-HA) and protamine forms through an electrostatic-driven physical assembly, which is chemically crosslinked to acquire the collaboratively assembled nanocapsule (cNC) concurrently. The obtained cNC displays significantly higher stability than NC. Functional moieties as flexible assembly units can be easily equipped on cNC for long circulation, active targeting, or controlled siRNA release. cNC-F decorated with folic acid, a macrophage-targeting ligand promotes the siRNA accumulation in the activated macrophages in the liver of the obese mouse model. cNC-F loaded with siRNA targeting inflammatory indicators efficiently control the macrophage inflammatory response by reducing the expression of the inflammatory proteins (> 40% reduction) and ameliorating the insulin resistance symptoms of the obese mice.

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Section: Introductionmentioning

confidence: 99%

Collaborative assembly-mediated siRNA delivery for relieving inflammation-induced insulin resistance

Shen

Zhang

et al. 2020

Nano Res.

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“…Changes in ion concentrations, such as reductions in intracellular K + , can trigger the activation of NLPR3 [22], whereas the inhibition of Ca 2+ influx can reduce the activation of the NLRP3 inflammasome [23]. Na + may not be required for activation of the NLRP3 inflammasome, but a study found that Na + influx relies on K + influx in the activation of the NLRP3 inflammasome, and Cl − channel inhibitors (such as flufenamic acid, IAA94, DIDS, and NPPB) may inhibit NLRP3 [22,[24][25][26]. In addition, NLRP3 can be activated by the production of reactive oxygen species, lysosomal instability, post-translational modifications of NLRP3, and activation of human caspase-4/5 and mouse caspase-11 [27][28][29][30][31].…”

Section: The Nlrp3 Inflammasomementioning

confidence: 99%

Modulatory Mechanisms of the NLRP3 Inflammasomes in Diabetes

Ding

et al. 2019

Biomolecules

158

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The inflammasome is a multiprotein complex that acts to enhance inflammatory responses by promoting the production and secretion of key cytokines. The best-known inflammasome is the NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin domain-containing 3) inflammasome. The evidence has shown that the NLRP3 inflammasome, IL-1β, thioredoxin-interacting protein (TXNIP), and pyroptosis play vital roles in the development of diabetes. This review summarizes the regulation of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) by NLRP3 via modulation of glucose tolerance, insulin resistance, inflammation, and apoptosis mediated by endoplasmic reticulum stress in adipose tissue. Moreover, NLRP3 participates in intestinal homeostasis and inflammatory conditions, and NLRP3-deficient mice experience intestinal lesions. The diversity of an individual’s gut microbiome and the resultant microbial metabolites determines the extent of their involvement in the physiological and pathological mechanisms within the gut. As such, further study of the interaction between the NLRP3 inflammasome and the complex intestinal environment in disease development is warranted to discover novel therapies for the treatment of diabetes.

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“…Collectively, these results confirmed the effective gene editing of the NLRP3 gene as mediated by CLANs both in vitro and in vivo . It was further demonstrated that some acute inflammations, such as lipopolysaccharide (LPS)‐induced septic shock, monosodium urate crystal (MSU)‐induced peritonitis, and HFD‐T2D, could be alleviated by disrupting the expression of NLRP3 in macrophages as well (Figure ) …”

Section: Non‐viral Vectors Of Crispr‐cas9mentioning

confidence: 99%

“…T2D mice subjected to fasting glucose were treated with CLAN mCas9/gNLRP3 or other formulations. Reproduced with permission…”

Section: Non‐viral Vectors Of Crispr‐cas9mentioning

confidence: 99%

Delivery of CRISPR/Cas9 for therapeutic genome editing

Wan

Xin

et al. 2019

The Journal of Gene Medicine

101

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The clustered, regularly‐interspaced, short palindromic repeat (CRISPR)‐associated nuclease 9 (CRISPR/Cas9) is emerging as a promising genome‐editing tool for treating diseases in a precise way, and has been applied to a wide range of research in the areas of biology, genetics, and medicine. Delivery of therapeutic genome‐editing agents provides a promising platform for the treatment of genetic disorders. Although viral vectors are widely used to deliver CRISPR/Cas9 elements with high efficiency, they suffer from several drawbacks, such as mutagenesis, immunogenicity, and off‐target effects. Recently, non‐viral vectors have emerged as another class of delivery carriers in terms of their safety, simplicity, and flexibility. In this review, we discuss the modes of CRISPR/Cas9 delivery, the barriers to the delivery process and the application of CRISPR/Cas9 system for the treatment of genetic disorders. We also highlight several representative types of non‐viral vectors, including polymers, liposomes, cell‐penetrating peptides, and other synthetic vectors, for the therapeutic delivery of CRISPR/Cas9 system. The applications of CRISPR/Cas9 in treating genetic disorders mediated by the non‐viral vectors are also discussed.

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

Cited by 145 publications

References 63 publications

Collaborative assembly-mediated siRNA delivery for relieving inflammation-induced insulin resistance

Collaborative assembly-mediated siRNA delivery for relieving inflammation-induced insulin resistance

Modulatory Mechanisms of the NLRP3 Inflammasomes in Diabetes

Delivery of CRISPR/Cas9 for therapeutic genome editing

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