Targeted delivery of nano-encapsulated anti-inflammatory agent represents a promising while challenging strategy in the treatment of rheumatoid arthritis (RA). Pro-inflammatory macrophages play a major role in the pathogenesis of RA. In this study, we investigated the effect of a macrophage-targeted pH-sensitive nanoparticle on collagen-induced arthritis (CIA) in mice. To target macrophage, all-trans-retinal was conjugated into dextran backbone through pH-sensitive hydrazone bond, then grafted with galactose (GDR). This nanoparticle was used for the encapsulation of triptolide (TPT), a potent anti-inflammatory compound isolated from Chinese herb. As expected, GDR nanoparticles preferentially accumulated in the inflammatory tissues. Treatment with GDR-TPT nanoparticles resulted in a marked decrease in the infiltration of CD3 T cells and F4/80 macrophages and reduction of the expression of TNF-α, IL-6 and IL-1β in the inflamed lesions of CIA mice. Furthermore, Th1 and Th17 responses were also inhibited. Importantly, anti-arthritic effect of TPT was markedly enhanced while its toxic effect was attenuated by encapsulating with GDR. GDR by itself also had moderate effect in the inhibition of arthritis, due to its intrinsic anti-inflammatory property. Therefore, our results clearly show that GDR-TPT nanoparticle may represent a promising drug delivery system for the treatment of RA.