A novel therapeutic strategy for cartilage diseases based on lipid nanoparticle-RNAi delivery system.
A novel therapeutic strategy for cartilage diseases based on lipid nanoparticle-RNAi delivery system.
复制标题
基于脂质纳米粒子-RNAi递送系统的软骨疾病新治疗策略
DOI：
10.2147/ijn.s142797
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发表时间：
2018
影响因子：
8
通讯作者：
Wei L
中科院分区：
文献类型：
--
作者：
Wang S;Wei X;Sun X;Chen C;Zhou J;Zhang G;Wu H;Guo B;Wei L
软骨退化影响着数百万人，但防止其退化是一个巨大的挑战。尽管 RNA 干扰 (RNAi) 已通过沉默特定基因用于人体试验，但软骨 RNAi 迄今为止还不可能实现，因为软骨是无血管且非常致密的组织，渗透性非常低。本研究的目的是开发并验证一种新型脂质纳米颗粒 (LNP)-siRNA 递送系统，该系统可以通过敲除特定基因来预防软骨退化。在体外和离体评估 LNP 转染效率。印度刺猬 (Ihh) 与软骨退化有关。在手术诱发的骨关节炎 (OA) 大鼠模型中评估了 LNP-Ihh siRNA 复合物对软骨退变的体内作用。在体外，LNP-siRNA组中100%的软骨细胞被siRNA转染。根据细胞培养结果，即使在经过LNP-beacon处理的软骨组织培养物的深层中也可以检测到红色阳性信号。体内数据表明，LNP 对软骨具有特异性，因为荧光分子断层扫描和共聚焦显微镜在注射 LNP 信标的关节软骨中检测到阳性信号，但在滑膜表面没有检测到阳性信号。在 OA 大鼠模型中，关节内注射 LNP-Ihh siRNA 可减缓 OA 进展，PCR 结果显示 LNP-Ihh siRNA 对合成代谢产生积极影响，对分解代谢产生负面影响。这项研究表明，我们的 LNP-RNAi 递送系统具有显着的软骨保护作用，可以减轻软骨退化，并有望成为通过敲除特定基因来治疗软骨疾病的强大工具。
Cartilage degeneration affects millions of people but preventing its degeneration is a big challenge. Although RNA interference (RNAi) has been used in human trials via silencing specific genes, the cartilage RNAi has not been possible to date because the cartilage is an avascular and very dense tissue with very low permeability. The objective of this study was to develop and validate a novel lipid nanoparticle (LNP)-siRNA delivery system that can prevent cartilage degeneration by knocking down specific genes. LNP transfection efficiency was evaluated in vitro and ex vivo. Indian Hedgehog (Ihh) has been correlated with cartilage degeneration. The in vivo effects of LNP-Ihh siRNA complexes on cartilage degeneration were evaluated in a rat model of surgery-induced osteoarthritis (OA). In vitro, 100% of chondrocytes were transfected with siRNA in the LNP-siRNA group. In accordance with the cell culture results, red positive signals could be detected even in the deep layer of cartilage tissue cultures treated by LNP-beacon. In vivo data showed that LNP is specific for cartilage, since positive signals were detected by fluorescence molecular tomography and confocal microscopy in joint cartilage injected with LNP-beacon, but not on the surface of the synovium. In the rat model of OA, intraarticular injection of LNP-Ihh siRNA attenuated OA progression, and PCR results showed LNP-Ihh siRNA exerted a positive impact on anabolic metabolism and negative impact on catabolic metabolism. This study demonstrates that our LNP-RNAi delivery system has a significantly chondroprotective effect that attenuates cartilage degeneration and holds great promise as a powerful tool for treatment of cartilage diseases by knocking down specific genes.