Infiltration of inflammatory cells, especially the M1 macrophages that secrete various types of inflammation cytokines, play crucial roles in the pathogenesis of rheumatoid arthritis (RA). To relief synovial inflammation, M1 macrophages must be eliminated or switched to anti-inflammatory M2 phenotype. We herein developed folic acid modified silver nanoparticles (FA-AgNPs) that can actively deliver into M1 macrophages to synergistically induce M1 macrophages reduction and M2 macrophages polarization for effective RA treatment. The AgNPs was facilely prepared, PEGylated and modified with FA to realize M1 macrophages targeting delivery via folate receptor overexpressed on M1 macrophages surface. After entering cells, FA-AgNPs dissolved and released Ag⁺ in response to intracellular glutathione (GSH), which is the key element to exert a series of anti-inflammatory functions, such as M1 macrophages apoptosis and reactive oxygen species (ROS) scavenging to facilitate M2 macrophages polarization, both of which contributed to RA treatment. This nano-system could passively accumulate into inflamed joints, permit potent anti-inflammatory activity, and impose strong therapeutic efficacy in mice RA models with high biosafety. After treatment, FA-AgNPs could be gradually cleared from the body mainly via feces without tissue accumulation, and did not show any appreciable long-term toxicity. This work declares the first example of using bio-active nanoparticles for RA treatment without loading any drugs, and highlights the potential of FA-AgNPs for targeted RA therapy via simultaneous M1 macrophage apoptosis and M1-to-M2 macrophages re-polarization.

炎症细胞的浸润，尤其是分泌各种类型炎症细胞因子的M1巨噬细胞，在类风湿关节炎（RA）的发病机理中起着至关重要的作用。为了缓解滑膜炎症，必须消除M1巨噬细胞或将其转变为抗炎症M2表型。我们在本文中开发了叶酸修饰的银纳米颗粒（FA-AgNPs），可以有效地将其递送到M1巨噬细胞中以协同诱导M1巨噬细胞减少和M2巨噬细胞极化，从而有效治疗RA。AgNPs易于制备，聚乙二醇化并用FA修饰，以实现通过在M1巨噬细胞表面过表达的叶酸受体靶向递送的M1巨噬细胞。进入细胞后，FA-AgNPs溶解并释放Ag ⁺对细胞内谷胱甘肽（GSH）的响应，后者是发挥一系列抗炎功能的关键元素，例如M1巨噬细胞凋亡和活性氧（ROS）清除以促进M2巨噬细胞极化，这两者均有助于RA治疗。这种纳米系统可以被动地积聚在发炎的关节中，具有强大的抗炎活性，并在具有高生物安全性的小鼠RA模型中具有强大的治疗功效。治疗后，FA-AgNPs可以通过粪便逐渐从体内清除，而没有组织积聚，并且没有显示任何明显的长期毒性。这项工作宣布了使用生物活性纳米粒子进行RA治疗而无需加载任何药物的第一个例子，