M1 Macrophage-Targeted Engineered Ginseng Stems and Leaves-Derived Extracellular Vesicles Delivery System for Alleviating Rheumatoid Arthritis

Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, oxidative stress damage, and joint destruction. Current treatments often face challenges including limited targeting efficacy and systemic side effects. To develop a novel targeted therapy for RA, this study constructed a functionalized extracellular vesicle system by engineering ginseng stems and leaves-derived extracellular vesicles (EVs) with hyaluronic acid (HA) modification and curcumin (Cur) loading (Cur@EVs-PH). Structurally, the EVs-PH drug-loaded nano-platform integrates the remarkable anti-inflammatory and antioxidant properties of EVs with the prolonged circulation capacity conferred by PEG. This design further capitalizes on the targeting ability of hyaluronic acid (HA), thereby providing a robust structural foundation for the efficient delivery of therapeutics to disease sites. Our results demonstrated that the designed system achieved enhanced inflammatory targeting through CD44 receptor-mediated accumulation and exhibited potent anti-inflammatory and antioxidant activities. In CIA model, Cur@EVs-PH significantly alleviated joint swelling, reduced pathological scores, and normalized immune organ indices. Mechanistic studies revealed that the therapeutic effects were mediated through suppression of pro-inflammatory cytokines and promotion of macrophage M2 polarization. This integrated strategy combining natural extracellular vesicles, targeted modification, and active drug loading provides a promising platform for the treatment of RA and other inflammatory diseases.