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Here, carbon dots (CDs) with multienzyme activity and inflammation\u2010targeting capabilities are designed to deliver methotrexate (MTX) for synergistic RA treatment. Specifically, positively charged CDs with porphyrin iron cores and amino\u2010functionalized surfaces are synthesized to simultaneously scavenge hydrogen peroxide, superoxide anions, and hydroxyl radicals. Conjugation of MTX\u2010loaded CDs with polyethylene glycol (CDs2\u2010P@M) via Schiff base reaction significantly prolongs in vivo circulation time. In collagen\u2010induced arthritis rats, CDs2\u2010P@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.<\/jats:p>","DOI":"10.1002\/smll.202412491","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T12:51:49Z","timestamp":1743857509000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Inflammation\u2010Targeting Multienzyme Activity Carbon Dots Loaded with Methotrexate for Synergistic Immunotherapy in Rheumatoid Arthritis"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1705-8952","authenticated-orcid":false,"given":"Qian","family":"He","sequence":"first","affiliation":[{"name":"Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Third Hospital of Shanxi Medical University Tongji Shanxi Hospital  Taiyuan 030032 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