PDF(Pubmed)
Abstract：
Normalizing inflamed soils including reactive oxygen species (ROS), nitric oxide (NO), cell-free DNA, and regulating inflammation-related seeds such as macrophages, neutrophils, fibroblasts, represent a promising strategy to maintain synovial tissue homeostasis for rheumatoid arthritis (RA) treatment. Herein, ROS scavenging amphiphilic block copolymer PEGylated bilirubin and NO-scavenging PEGylated o-phenylenediamine were fabricated to self-assemble into a dually responsive nanoparticle loaded with JAK inhibitor notopterol (Not@BR/oPDA-PEG, NBOP NPs). The simultaneous ROS and NO depletion combined with JAK-STAT pathway inhibition could not only promote M2 polarization to reduce further ROS and NO generation, but also decrease cytokines and chemokines to prevent immune cell recruitment. Specifically, NBOP NPs responded to high level ROS and NO, and disintegrated to release notopterol in inflamed joints as the hydrophobic heads BR and oPDA were transformed into hydrophilic ones. The released notopterol could inhibit the JAK-STAT pathway of inflammatory cells to reduce the secretion of pro-inflammatory cytokines and chemokines. This strategy represented an effective way to regulate RA soils and seeds through breaking the positive feedback loop of inflammation aggravation, achieving an excellent anti-RA efficacy in a collagen-induced arthritis rat model. Taken together, our work offered a reference to adjust RA soils and seeds for enhanced RA treatment.
摘要：
包括活性氧(ROS)在内的土壤中的正火，一氧化氮（NO），无细胞DNA,并调节与炎症相关的种子，如巨噬细胞，中性粒细胞，成纤维细胞,代表了维持类风湿关节炎（RA）治疗滑膜组织稳态的有希望的策略。在这里，ROS清除两亲性嵌段共聚物聚乙二醇化胆红素和NO清除聚乙二醇化邻苯二胺被制造成自组装成负载有JAK抑制剂诺波特罗的双重响应纳米颗粒（Not@BR/oPDA-PEG，NBOPNPs)。同时ROS和NO耗竭结合JAK-STAT通路抑制不仅可以促进M2极化，进一步减少ROS和NO的生成，但也减少细胞因子和趋化因子，以防止免疫细胞募集。具体来说,NBOPNPs对高水平ROS和NO的反应，并随着疏水头BR和oPDA转化为亲水头而崩解，在接头中释放出诺普特罗。释放的诺普特罗可以抑制炎症细胞的JAK-STAT通路，减少促炎细胞因子和趋化因子的分泌。该策略代表了通过打破炎症加重的正反馈循环来调节RA土壤和种子的有效方法。在胶原诱导的关节炎大鼠模型中获得优异的抗RA功效。一起来看,我们的工作为调整RA土壤和种子以增强RA治疗提供了参考。
