ROS-mediated liposomal dexamethasone: a new FA-targeted nanoformulation to combat rheumatoid arthritis via inhibiting iRhom2/TNF-α/BAFF pathways,Nanoscale

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ROS-mediated liposomal dexamethasone: a new FA-targeted nanoformulation to combat rheumatoid arthritis via inhibiting iRhom2/TNF-α/BAFF pathways
Nanoscale ( IF 5.8 ) Pub Date : 2021-11-01 , DOI: 10.1039/d1nr05518f
Yanqin Song _{1,

2} , Muhammad Ismail ₃ , Qi Shan ₁ , Jianing Zhao ₁ , Yanping Zhu ₁ , Leiming Zhang ₁ , Yuan Du ₁ , Longbing Ling ₁

Affiliation

Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder that has seriously affected human health worldwide and its current management requires more successful therapeutic approaches. The combination of nanomedicines and pathophysiology into one system may provide an alternative strategy for precise RA treatment. In this work, a practical ROS-mediated liposome, abbreviated as Dex@FA-ROS-Lips that comprised synthetic dimeric thioether lipids (di-S-PC) and a surface functionalized with folic acid (FA), was proposed for dexamethasone (Dex) delivery. Incorporation with thioether lipids and a FA segment significantly improved the triggered release and improved the triggered release of cytotoxic Dex as well as the active targeting of RA, altering its overall pharmacokinetics and safety profiles in vivo. As proof, the designed Dex@FA-ROS-Lips demonstrated effective internalization by LPS-activated Raw264.7 macrophages with FA receptor overexpression and released Dex at the inflammatory site due to the ROS-triggered disassembly. Intravenous injection of this Dex@FA-ROS-Lips into adjuvant-induced arthritis (AIA) mice led to its incremental accumulation in inflamed joint tissues and significantly alleviated the cartilage destruction and joint swelling via suppression of proinflammatory cytokines (iRhom2, TNF-α and BAFF), as compared to the effect of commercial free Dex. Importantly, the Dex@FA-ROS-Lips nanoformulation showed better hemocompatibility with less adverse effects on the body weight and immune organ index of AIA mice. The anti-inflammatory mechanism of Dex@FA-ROS-Lips was further studied and it was found that it is possibly associated with the down-regulation of iRhom2 and the activation of the TNF-α/BAFF signaling pathway. Therefore, the integration of nanomedicines and the RA microenvironment using multifunctional Dex@FA-ROS-Lips shall be a novel RA treatment modality with full clinical potential, and based on the enhanced therapeutic effect, the signaling pathway of iRhom2/TNF-α/BAFF reasonably explained the mechanism of Dex@FA-ROS-Lips in anti-RA, which suggested a molecular target for RA therapy and other inflammatory diseases.

中文翻译：

ROS 介导的脂质体地塞米松：一种通过抑制 iRhom2/TNF-α/BAFF 通路来对抗类风湿性关节炎的新型 FA 靶向纳米制剂

类风湿性关节炎 (RA) 是一种自身免疫性炎症性疾病，严重影响了全世界人类的健康，目前的管理需要更成功的治疗方法。将纳米药物和病理生理学结合到一个系统中，可能为精确的 RA 治疗提供另一种策略。在这项工作中，为地塞米松（Dex ）交货。硫醚脂质和 FA 片段的结合显着改善了触发释放并改善了细胞毒性 Dex 的触发释放以及 RA 的主动靶向，改变了其在体内的整体药代动力学和安全性特征. 作为证据，设计的 Dex@FA-ROS-Lips 证明了 LPS 激活的 Raw264.7 巨噬细胞有效内化，FA 受体过度表达，并由于 ROS 触发的拆卸而在炎症部位释放 Dex。静脉注射本塞米松@ FA-ROS-嘴唇的成佐剂诱导的关节炎（AIA）的小鼠导致其增量积累在发炎的关节组织和显著缓解了软骨破坏和关节肿胀经由与商业免费 Dex 的效果相比，抑制促炎细胞因子（iRhom2、TNF-α 和 BAFF）。重要的是，Dex@FA-ROS-Lips 纳米制剂显示出更好的血液相容性，对 AIA 小鼠的体重和免疫器官指数的不利影响较小。进一步研究了 Dex@FA-ROS-Lips 的抗炎机制，发现它可能与 iRhom2 的下调和 TNF-α/BAFF 信号通路的激活有关。因此，纳米药物与使用多功能 Dex@FA-ROS-Lips 的 RA 微环境的整合应该是一种具有充分临床潜力的新型 RA 治疗方式，并基于增强的治疗效果，iRhom2/TNF-α/BAFF 的信号通路合理解释了 Dex@FA-ROS-Lips 抗 RA 的机制，

更新日期：2021-11-30

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