Inflammation Targeting and Responsive Multifunctional Drug‐Delivery Nanoplatforms for Combined Therapy of Rheumatoid Arthritis

Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent inflammation, joint swelling, pain, and progressive joint destruction. Methotrexate (MTX) is the standard first‐line treatment for RA, but its clinical application is hindered by poor water solubility and non‐specific delivery. In this work, a multifunctional drug‐delivery nanoplatform that targets both macrophages and tumor necrosis factor α (TNFα) is developed to enhance the therapeutic efficacy of MTX in RA. The nanoplatform consists of folic acid (FA, for macrophage targeting) and a TNFα‐specific Aptamer (TNFα‐Apt), facilitating a dual‐targeting strategy that significantly improves the accumulation of MTX at the sites of RA lesions (≈3.5‐fold). Moreover, the manganese dioxide (MnO₂) and polydopamine (PDA) coatings on the nanoplatform effectively scavenge reactive oxygen species (ROS), generate oxygen, and promote the polarization of pro‐inflammatory M1 macrophages to the anti‐inflammatory M2 macrophages. This shift in macrophage polarization restores the expression of key inflammatory cytokines, improving the local inflammatory microenvironment. Ultimately, the nanoplatform significantly ameliorates the inflammation and joint damage in a collagen‐induced arthritis (CIA) model, suggesting that this multi‐target combination therapy holds considerable potential for the treatment of RA in vivo.