Inflammation‐Targeting Multienzyme Activity Carbon Dots Loaded with Methotrexate for Synergistic Immunotherapy in Rheumatoid Arthritis

Abstract In rheumatoid arthritis (RA), excessive reactive oxygen species (ROS) and chronic inflammation drive damage to the synovium, cartilage, and bone. Developing precise and synergistic therapy for RA is crucial for improving remission rates. Here, carbon dots (CDs) with multienzyme activity and inflammation‐targeting capabilities are designed to deliver methotrexate (MTX) for synergistic RA treatment. Specifically, positively charged CDs with porphyrin iron cores and amino‐functionalized surfaces are synthesized to simultaneously scavenge hydrogen peroxide, superoxide anions, and hydroxyl radicals. Conjugation of MTX‐loaded CDs with polyethylene glycol (CDs2‐P@M) via Schiff base reaction significantly prolongs in vivo circulation time. In collagen‐induced arthritis rats, CDs2‐P@M accumulates in the diseased joints, reducing ROS and inflammatory cytokines, reprogramming macrophage phenotypes, inhibiting osteoclast activation, and markedly improving arthritis symptoms. This approach targets the RA microenvironment, minimizing MTX toxicity and effectively reshaping immune homeostasis, halting inflammation and tissue destruction, thus offering a new paradigm for RA immunotherapy.