靶向关节炎关节中的巨噬细胞和破骨细胞的细胞凋亡可有效对抗晚期炎症性关节炎。

Targeted apoptosis of macrophages and osteoclasts in arthritic joints is effective against advanced inflammatory arthritis.

机构信息

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China.

Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China.

出版信息

Nat Commun. 2021 Apr 12;12(1):2174. doi: 10.1038/s41467-021-22454-z.

Insufficient apoptosis of inflammatory macrophages and osteoclasts (OCs) in rheumatoid arthritis (RA) joints contributes toward the persistent progression of joint inflammation and destruction. Here, we deliver celastrol (CEL) to selectively induce apoptosis of OCs and macrophages in arthritic joints, with enzyme-responsive nanoparticles (termed PRNPs) composed of RGD modified nanoparticles (termed RNPs) covered with cleavable PEG chains. CEL-loaded PRNPs (CEL-PRNPs) dually target OCs and inflammatory macrophages derived from patients with RA via an RGD-αvβ3 integrin interaction after PEG cleavage by matrix metalloprotease 9, leading to increased apoptosis of these cells. In an adjuvant-induced arthritis rat model, PRNPs have an arthritic joint-specific distribution and CEL-PRNPs efficiently reduce the number of OCs and inflammatory macrophages within these joints. Additionally, rats with advanced arthritis go into inflammatory remission with bone erosion repair and negligible side effects after CEL-PRNPs treatment. These findings indicate potential for targeting chemotherapy-induced apoptosis in the treatment of advanced inflammatory arthritis.

类风湿关节炎（RA）关节中炎症巨噬细胞和破骨细胞（OCs）的凋亡不足导致关节炎症和破坏的持续进展。在这里，我们使用雷公藤红素（CEL）来选择性地诱导关节炎关节中 OC 和巨噬细胞的凋亡，使用由 RGD 修饰的纳米颗粒（称为 RNPs）组成的酶响应纳米颗粒（称为 PRNPs），其表面覆盖可切割的 PEG 链。在基质金属蛋白酶 9 切割 PEG 后，通过 RGD-αvβ3 整联蛋白相互作用，CEL 负载的 PRNPs（CEL-PRNPs）双重靶向源自 RA 患者的 OC 和炎性巨噬细胞，导致这些细胞的凋亡增加。在佐剂诱导的关节炎大鼠模型中，PRNPs 具有关节炎关节特异性分布，CEL-PRNPs 可有效减少这些关节中的 OC 和炎性巨噬细胞数量。此外，在 CEL-PRNPs 治疗后，患有晚期关节炎的大鼠进入炎症缓解期，骨侵蚀得到修复，且副作用可忽略不计。这些发现表明，针对化疗诱导的细胞凋亡可能为治疗晚期炎症性关节炎提供一种新的方法。