Folate-decorated nanoparticles deliver bulleyaconitine A to inflammatory macrophages for rheumatoid arthritis therapy.

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease driven by synovial inflammatory cell infiltration and progressive joint erosion. Macrophages undergo a pathological shift toward an M1 pro-inflammatory phenotype, which plays a critical role in the progression of the disease. Modulation of M1 macrophages may be a promising therapeutic strategy. Herein, we developed folic acid-functionalized PLGA nanoparticles (FA-PLGA NPs) for targeted delivery of an anti-inflammatory natural compound, bulleyaconitine A (BLA), into M1 macrophages. The nanoparticles exhibited a mean hydrodynamic diameter of 151.91 ± 5.41 nm with a polydispersity index of 0.153 ± 0.016, a negative zeta potential (-13.50 ± 0.82 mV), a high encapsulation efficiency of 90.0%, and excellent colloidal stability. In vitro, FA-PLGA NPs were efficiently internalized by M1-polarized RAW264.7 macrophages via folate receptor-mediated endocytosis, and the uptake level was 7.79-fold higher than non-targeted NPs. Exposure to the NPs significantly reduced the population of CD86-positive M1 cells and decreased iNOS expression while increasing Arg-1 expression. Transcriptomic analysis revealed downregulation of pro-inflammatory and tissue-destructive pathways and upregulation of myeloid differentiation and immune regulation genes. In an adjuvant-induced arthritis rat model, FA-PLGA NPs treatment resulted in significant alleviation of paw swelling, joint destruction, and cartilage proteoglycan loss, as well as a decrease in the levels of serum IL-6 and TNF-α. Encouragingly, the nanoparticle formulation exhibited favorable in vivo safety, with no observable adverse effects on major organs. Collectively, FA‑PLGA NPs effectively modulated M1 macrophages and achieved potent anti‑arthritic efficacy with improved safety, demonstrating their potential as a nanotherapeutic for RA management.