Rheumatoid arthritis (RA) is an autoimmune disease characterized by hypoxia and reactive oxygen species (ROS) overexpression, which cause inflammatory cascade and cartilage erosion. As representative inflammatory cells, macrophages produce many inflammatory factors, and intracellular ROS is abnormally elevated. Therefore, improving hypoxia and scavenging ROS are essential to inhibit the inflammatory response of synovial macrophages and cartilage destruction. Due to the complex microenvironment of RA and the single action of most anti-inflammatory and antioxidant drugs, as well as the difficulty in reversing the microenvironment with current formulations developed for ROS clearance, it is necessary to develop multifunctional nanoparticles (NPs) to achieve better therapeutic effects. In this work, we constructed a delivery system called PCM@MnO NPs, which could reduce inflammatory factors and improve the RA environment through multifunctional synergistic effects such as eliminating ROS and generating oxygen. Specifically, chondroitin sulfate was used to form NPs with methotrexate (MTX) through electrostatic interactions and hydrogen bonding and further loaded with MnO to form CM@MnO NPs. Furthermore, modification of polydopamine on the surface of CM@MnO NPs improved the stability of the formulation and extended the cycle time. Under the acidic (pH 6.5) microenvironment of RA, polydopamine shells were dissociated. Chondroitin sulfate could target inflammatory macrophages via the CD44 receptor and subsequently release MTX and MnO under low-intracellular-pH (pH 5.2) conditions. MnO could decompose and consume ROS and further produce oxygen in the process of decomposing HO, alleviating the hypoxic microenvironment of RA. In addition, MTX could also inhibit the secretion of cytokines. Overall, by regulating the RA microenvironment through the various synergistic effects mentioned above, it could promote macrophage polarization and alleviate RA progression. The experimental results in vitro and in vivo indicated that pH-responsive PCM@MnO NPs could accumulate in inflammatory joints by the extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration (ELVIS) effect, enhance the precise delivery of MTX by targeting RA macrophages, and effectively alleviate the progression of disease and reduce the symptoms of collagen-induced arthritis mouse models. In general, using multifunctional synergistic therapy for RA is an effective potential strategy.