Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease that results in synovitis, cartilage destruction, and even loss of joint function. The frequent and long-term administration of anti-rheumatic drugs often leads to obvious adverse effects and patient non-compliance. Therefore, to specifically deliver dexamethasone (Dex) to inflamed joints and reduce the administration frequency of Dex, we developed Dex-loaded reactive oxygen species (ROS)-responsive nanoparticles (Dex/Oxi-αCD NPs) and folic acid (FA) modified Dex/Oxi-αCD NPs (Dex/FA-Oxi-αCD NPs) and validated their anti-inflammatory effect in vitro and in vivo. In vitro study demonstrated that these NPs can be effectively internalized by activated macrophages and the released Dex from NPs significantly downregulated the expression of iRhom2, TNF-α, and BAFF in activated Raw264.7. In vivo experiments revealed that Dex/Oxi-αCD NPs, especially Dex/FA-Oxi-αCD NPs significantly accumulated at inflamed joints in collagen-induced arthritis (CIA) mice and alleviated the joint swelling and cartilage destruction. Importantly, the expression of iRhom2, TNF-α, and BAFF in the joint was inhibited by intravenous injection of Dex/Oxi-αCD NPs and Dex/FA-Oxi-αCD NPs. Collectively, our data revealed that Dex-loaded ROS-responsive NPs can target inflamed joints and attenuate arthritis, and the 'iRhom2-TNF-α-BAFF' pathway plays an important role in the treatment of RA with the NPs, suggesting that this pathway may be a novel target for RA therapy.

中文翻译：

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通过抑制iRhom2 /TNF-α/ BAFF信号传导途径，负载活性氧的地塞米松负载纳米颗粒可用于类风湿关节炎的靶向治疗。

类风湿关节炎（RA）是一种免疫介导的炎症性疾病，可导致滑膜炎，软骨破坏，甚至丧失关节功能。经常和长期服用抗风湿药通常会导致明显的不良反应和患者违规行为。因此，为了将地塞米松（Dex）专门递送至发炎的关节并减少Dex的给药频率，我们开发了负载Dex的活性氧（ROS）响应纳米颗粒（Dex /Oxi-αCDNPs）和叶酸（FA）修饰的Dex /Oxi-αCDNPs（Dex /FA-Oxi-αCDNPs），并在体内和体外验证了它们的抗炎作用。体外研究表明，这些NP可以被活化的巨噬细胞有效地内在化，并且从NP释放的Dex显着下调了活化的Raw264.7中iRhom2，TNF-α和BAFF的表达。体内实验表明，Dex /Oxi-αCDNPs，尤其是Dex /FA-Oxi-αCDNPs在胶原诱导的关节炎（CIA）小鼠的发炎关节处大量积聚，减轻了关节肿胀和软骨破坏。重要的是，静脉注射Dex /Oxi-αCDNP和Dex /FA-Oxi-αCDNP可抑制关节中iRhom2，TNF-α和BAFF的表达。总体而言，我们的数据表明，Dex加载的ROS反应性NPs可以靶向发炎的关节并减轻关节炎，“iRhom2-TNF-α-BAFF”途径在NPs治疗RA中起着重要作用，表明该途径可能是RA治疗的新靶标。尤其是Dex /FA-Oxi-αCDNP在胶原诱导的关节炎（CIA）小鼠发炎的关节处大量积聚，减轻了关节肿胀和软骨破坏。重要的是，静脉注射Dex /Oxi-αCDNP和Dex /FA-Oxi-αCDNP可抑制关节中iRhom2，TNF-α和BAFF的表达。总体而言，我们的数据表明，Dex加载的ROS反应性NPs可以靶向发炎的关节并减轻关节炎，“iRhom2-TNF-α-BAFF”途径在NPs治疗RA中起着重要作用，表明该途径可能是RA治疗的新靶标。尤其是Dex /FA-Oxi-αCDNP在胶原诱导的关节炎（CIA）小鼠发炎的关节处大量积聚，减轻了关节肿胀和软骨破坏。重要的是，静脉注射Dex /Oxi-αCDNP和Dex /FA-Oxi-αCDNP可抑制关节中iRhom2，TNF-α和BAFF的表达。总体而言，我们的数据表明，Dex加载的ROS反应性NPs可以靶向发炎的关节并减轻关节炎，“iRhom2-TNF-α-BAFF”途径在NPs治疗RA中起着重要作用，表明该途径可能是RA治疗的新靶标。