Treatment of Ulcerative Colitis by Cationic Liposome Delivered NLRP3 siRNA.
Treatment of Ulcerative Colitis by Cationic Liposome Delivered NLRP3 siRNA.
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阳离子脂质体介导NLRP 3 siRNA治疗溃疡性结肠炎的研究
DOI：
10.2147/ijn.s413149
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发表时间：
2023
影响因子：
8
通讯作者：
中科院分区：
文献类型：
--
作者：
NLRP3 炎性体的异常激活与溃疡性结肠炎（UC）的发生和发展有关。然而，理想的药物和递送系统仍然是限制靶向 NLRP3 炎症球体治疗 UC 的重要因素。通过递送 siRNA 进行基因治疗可有效治疗多种疾病。因此，使用理想的载体递送 siNLRP3 治疗 UC 是必要的。
以阳离子脂质体（CLP/siNLRP3）为基础开发的纳米颗粒可递送 siNLRP3。它们抑制 NLRP3 炎性体活化的能力通过 Western 印迹（WB）和酶联免疫吸附试验（ELISA）进行了监测。通过WB和免疫荧光检测了LPS诱导的腹腔巨噬细胞（PMs）中ASC寡聚化的情况。此外，我们还通过检测NLRP3水平、促炎细胞因子表达和疾病相关指数（DAI），评估了CLP/siNLRP3对葡聚糖硫酸钠（DSS）诱导的UC的作用。流式细胞术（FCM）用于检测巨噬细胞和T细胞的含量。最后，我们评估了CLP/siNLRP3的安全性。
制备的CLP呈球形，粒径小（94 nm），渗透性低。CLP能有效保护siNLRP3不被降解，然后将siNLRP3送入PM，抑制NLRP3炎性体的激活。此外，CLP/siNLRP3 还能抑制 PMs 中成熟 IL-1β 和 IL-18 的分泌，从而达到良好的抗炎效果。在体内，CLP/siNLRP3能有效缓解UC小鼠的肠道损伤，其原因在于下调了IL-1β和IL-18的水平，抑制了巨噬细胞和其他免疫细胞的浸润，以及M1巨噬细胞的极化。最后，组织切片的病理测试和血液生化测试表明，CLP/siNLRP3 没有明显的毒性作用。
我们介绍了一种在体外和体内高效、安全、稳定地递送 siRNA 的前瞻性方法，发现它在以 RNA 沉默的方式治疗 NLRP3 驱动的疾病方面具有巨大潜力。
The abnormal activation of NLRP3 inflammasome is related to the occurrence and development of ulcerative colitis (UC). However, the ideal drug and delivery system remain important factors limiting the targeting of NLRP3 inflammasome in UC therapy. Gene therapy by delivering siRNA is effective in treating various diseases. Therefore, delivering siNLRP3 using an ideal vector for UC treatment is necessary. Nanoparticles delivering siNLRP3 were developed based on cationic liposome (CLP/siNLRP3). Their ability to inhibit NLRP3 inflammasome activation was monitored using Western blot (WB) and Enzyme-linked Immunosorbent Assay (ELISA). The ASC oligomerization in LPS-primed peritoneal macrophages (PMs) was detected by WB and immunofluorescence. Moreover, we assessed the role of CLP/siNLRP3 on dextran sodium sulfate (DSS)-induced UC by examining NLRP3 levels, pro-inflammatory cytokines expression, and disease-associated index (DAI). Flow cytometry (FCM) was used to detect the contents of macrophages and T cells. Finally, we assessed the safety of CLP/siNLRP3. The prepared CLP was spherical, with a small particle size (94 nm) and low permeability. The CLP could efficiently protect siNLRP3 from degradation and then deliver siNLRP3 into PMs, inhibiting NLRP3 inflammasome activation. Also, the CLP/siNLRP3 could inhibit the secretion of mature IL-1β and IL-18 from PMs, thereby achieving a favorable anti-inflammation effect. In vivo, CLP/siNLRP3 could effectively alleviate intestinal injury in UC mice, which was attributed to down-regulating levels of IL-1β and IL-18, inhibiting infiltration of macrophages and other immune cells, and the polarization of M1 macrophages. Finally, pathological testing of tissue sections and blood biochemical tests showed no significant toxic effects of CLP/siNLRP3. We introduced a prospective approach for the efficient delivery of siRNA in vitro and in vivo with high safety and stability, which was found to have great potential in treating NLRP3-driven diseases in an RNA-silencing manner.
影响因子：
39.3
作者：
Shang S;Monfregola L;Caruthers MH
通讯作者：
Caruthers MH
影响因子：
6.6
作者：
Luo X;Wang W;Dorkin JR;Veiseh O;Chang PH;Abutbul-Ionita I;Danino D;Langer R;Anderson DG;Dong Y
通讯作者：
Dong Y