Modulation of Macrophage Polarization in Rheumatoid Arthritis Therapy via Targeted Delivery of Bulleyaconitine A

Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects the joints, triggering persistent inflammation and progressive joint destruction. Bulleyaconitine A (BLA), an active compound derived from the traditional Chinese medicinal plant Aconitum bulleyanum, possesses strong anti-inflammatory properties. However, its clinical application is significantly hindered by poor solubility, lack of targeted delivery, and potential adverse effects. To address these limitations and enhance RA treatment efficacy, we developed an innovative reactive oxygen species (ROS)-responsive hierarchical targeting micelle system. By incorporating ROS-sensitive thioketal (TK) units and M1 macrophage-specific targeting groups (folic acid, FA), we engineered BLA-loaded ROS-responsive and M1 macrophage targeting polymeric micelles (TK-FA-BLA-MS). Transmission electron microscopy (TEM) and dynamic light scattering (DLS) characterization revealed that the TK-FA-BLA-MS micelles exhibited a uniform morphology, with an average hydrodynamic diameter of 89.47 ± 2.74 nm and a polydispersity index (PDI) of 0.21 ± 0.01, consistent with parameters optimal for targeted drug delivery systems. High-performance liquid chromatography (HPLC) analysis confirmed the micelles’ excellent drug-loading capacity and encapsulation efficiency, ensuring an efficient BLA delivery system. In vitro studies in an inflammatory model revealed that TK-FA-BLA-MS exhibited a strong response to the high ROS microenvironment. The system effectively inhibited the proliferation and ROS production of lipopolysaccharide-induced RAW264.7 (M1 type) macrophages and facilitated phenotype polarization from pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages. Furthermore, in a collagen-induced arthritis rat model, TK-FA-BLA-MS treatment yielded the following therapeutic benefits: a significant reduction in M1 macrophage marker expression in synovial tissue, an increase in M2 macrophage markers, decreased inflammatory cell infiltration, and improved bone and joint structural integrity. These findings suggest that this nanoscale system offers a promising therapeutic strategy for RA by enabling ROS-responsive drug release and precise macrophage targeting.