Research Advances in Targeted Modulation of Macrophage M1/M2 Polarization for the Treatment of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a disease of the immune system that leads to continuous synovial inflammation and the progressive breakdown of joints. As essential effector cells in innate immunity, macrophages can become either pro‐inflammatory M1 or anti‐inflammatory M2 phenotypes, playing a critical role in RA pathogenesis. A marked M1/M2 polarization imbalance exists in the synovial microenvironment of RA, in which excessive activation and accumulation of M1 macrophages serve as a key hub driving persistent inflammation, cartilage degradation, and bone erosion. Currently, conventional disease‐modifying antirheumatic drugs (DMARDs) with methotrexate (MTX) as the anchor agent remain the mainstay for RA management; however, approximately 30%‐40% of RA patients show an inadequate response to MTX, resulting in persistent synovial inflammation, progressive joint damage, and difficult‐to‐control disease. For macrophage‐directed phenotypic modulation in RA therapy, novel smart nanodelivery systems are a key research focus, while accumulating preclinical evidence supports the capacity of traditional Chinese medicine (TCM) to restore M1/M2 homeostasis. This review systematically summarizes the polarization mechanisms of macrophages in RA, their core pathological functions, and recent advances in targeting these cells as therapeutic strategies, therefore delivering novel insights and references for RA treatment through targeted changes in macrophage polarization.