类风湿性关节炎(RA)是一种复杂的免疫系统慢性疾病,关节严重发炎,滑膜增生,关节软骨,和骨骼损伤。在RA微环境中,涉及RA的细胞,过量产生的一氧化氮(NO),促炎细胞因子是高度相互作用和相互增强的,形成恶性循环,在RA的形成和发展中起着至关重要的作用。全面打破恶性循环,获取最大利益,我们已经开发了基于NO响应性透明质酸衍生物的中性粒细胞膜伪装的NO清除纳米颗粒,用于递送MTX。这些多功能纳米粒子(NNO-NP/MTX),通过继承来源细胞的膜功能,在体内施用时,在发炎部位具有延长的循环和特定的定位。值得注意的是,NNO-NPs/MTX可以通过外膜受体中和促炎细胞因子,清除NO,并且响应地分离释放用于RA相关细胞调节的MTX和用于RA位点润滑的HA。在胶原诱导的关节炎小鼠模型中,NNO-NPs/MTX具有显著的抗炎作用,可有效缓解滑膜增生、软骨破坏等RA特征性症状,实现对难治性RA的协同和增强治疗结果。因此,NNO-NP/MTX为RA的综合治疗提供了一个有前途且有效的平台。
Rheumatoid arthritis (RA) is a complicated chronic disorder of the immune system, featured with severe inflammatory joints, synovium hyperplasia, articular cartilage, and bone damage. In the RA microenvironment, RA-involved cells, overproduced nitric oxide (NO), and pro-inflammatory cytokines are highly interplayed and mutually reinforced, which form a vicious circle and play crucial roles in the formation and progression of RA. To comprehensively break the vicious circle and obtain the maximum benefits, we have developed neutrophil membrane-camouflaged NO scavenging nanoparticles based on an NO-responsive hyaluronic acid derivative for delivery of MTX. These multifunctional nanoparticles (NNO-NPs/MTX), by inheriting the membrane functions of the source cells, possess prolonged circulation and specific localization at the inflamed sites when administrated in the body. Remarkably, NNO-NPs/MTX can neutralize the pro-inflammatory cytokines via the outer membrane receptors, scavenge NO, and be responsively disassociated to release MTX for RA-involved cell regulation and HA for lubrication in the RA sites. In a collagen-induced arthritis mouse model, NNO-NPs/MTX exhibits a significant anti-inflammation effect and effectively alleviates the characteristic RA symptoms such as synovial hyperplasia and cartilage destruction, realizing the synergistic and boosted therapeutic outcome against intractable RA. Thus, NNO-NPs/MTX provides a promising and potent platform to integrately treat RA.