Nanoparticle-delivered siRNA targeting Bruton's tyrosine kinase for rheumatoid arthritis therapy
Nanoparticle-delivered siRNA targeting Bruton's tyrosine kinase for rheumatoid arthritis therapy
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纳米颗粒递送的 siRNA 靶向布鲁顿酪氨酸激酶用于类风湿性关节炎治疗
DOI：
10.1039/c9bm01025d
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发表时间：
2019
影响因子：
6.6
通讯作者：
Jun Wang
中科院分区：
文献类型：
--
作者：
Gui Zhao;An Liu;Yue Zhang;Zu-Qi Zuo;Zhi-Ting Cao;Hou-Bing Zhang;Cong-Fei Xu;Jun Wang
风湿性关节炎（RA）是一种全身性自身免疫性疾病，可导致不可逆的关节畸形. RA仍然无法治愈，目前的治疗方法，包括甲氨蝶呤和阿达木单抗，会导致严重的脱靶效应和全身免疫抑制，从而增加感染的风险。巨噬细胞和B细胞中的布鲁顿酪氨酸激酶（BTK）已被证明是RA的一个有希望的治疗靶点。然而，有效的BTK抑制需要高剂量的BTK抑制剂，这限制了它们的临床应用。小干扰RNA（siRNA）是一种有希望沉默特定基因的RNA干扰技术，已被用于多种疾病的治疗。为了将siRNA递送到巨噬细胞和B细胞中用于BTK基因沉默，我们采用阳离子脂质辅助的PEG-B-PLGA纳米颗粒（CLANs）来封装siRNA。我们证明了巨噬细胞和B细胞能够在体外和体内有效地摄取CLAN。此后，我们将靶向BTK的siRNA（siBTK）封装到CLANs中，表示为CLANsiBTK，并证明CLANsiBTK显著抑制巨噬细胞和B细胞中的BTK表达。在胶原蛋白诱导的小鼠关节炎模型中，CLANsiBTK治疗显著减少了关节炎症和其他RA症状，但没有显示出毒性，证明使用CLANsiBTK是一种有希望的RA治疗方法。
Rheumatoid arthritis (RA) is a systemic autoimmune disease that can cause irreversible joint deformity. There is still no cure for RA, and current therapeutics, including methotrexate and adalimumab, cause serious off-target effects and systemic immunosuppression, which in turn increases the risk of infection. Bruton's tyrosine kinase (BTK) in macrophages and B cells has been demonstrated to be a promising therapeutic target for RA. However, high doses of BTK inhibitors are required for efficient BTK suppression, which limits their clinical use. Small interfering RNA (siRNA) is promising for the silencing of specific genes and has been used for the treatment of multiple diseases. To deliver siRNA into macrophages and B cells for BTK gene silencing, we employed cationic lipid-assisted PEG-b-PLGA nanoparticles (CLANs) to encapsulate siRNA. We demonstrated that macrophages and B cells were able to efficiently ingest the CLANs both in vitro and in vivo. Thereafter, we encapsulated siRNA targeting BTK (siBTK) into the CLANs, denoted as CLANsiBTK, and demonstrated that CLANsiBTK significantly inhibited BTK expression in macrophages and B cells. In a collagen-induced mouse arthritis model, CLANsiBTK treatment dramatically reduced joint inflammation and other RA symptoms but showed no toxicity, proving that using CLANsiBTK is a promising approach for RA therapy.