Targeted co-delivery biomimetic nanoparticles reverse macrophage polarization for enhanced rheumatoid arthritis therapy

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, which is characterized by synovial inflammation and autoimmunity. The main cause of the disease is the imbalance of the proportion of pro-inflammatory macrophages (M1-type) and anti-inflammatory macrophages (M2-type) in the synovial tissues of the joint. To restore this balance, in our study, the interleukin-10 encoding anti-inflammatory cytokines (IL-10 pDNA) and chemotherapeutic drug dexamethasone sodium phosphate (DSP) were co-loaded into human serum albumin (HSA) preparing pDNA/DSP-NPs to actively target macrophages in synovium tissue to promote M1-M2 polarization. Confocal laser scanning microscope and western blot were used to demonstrate the targeting ability of co-delivery nanoparticles. In vivo, the real-time fluorescence imaging system and HPLC were used to study the tissue distribution and pharmacokinetics of nanoparticles, and the results showed that the accumulation of nanoparticles in the inflammatory joint site was higher. Its pharmacodynamics were evaluated in collagen-induced arthritis (CIA) rat model, and it demonstrated that the pDNA/DSP-NPs significantly reduced the expression of serum inflammatory factors and alleviated joint swelling and bone erosion, suggesting the favorable therapeutic effect. The synergistic treatment effect of IL-10 pDNA and DSP in this system was achieved by reducing the secretion of pro-inflammatory factors (TNF-α, IL-1β) and increasing the expression of anti-inflammatory factors (IL-10) to promote the M1-M2 polarization of macrophages. Our strategy is promising for co-delivery of gene drugs and chemical drugs by biomimetic natural materials to promote macrophages polarization so that to achieve synergically treatment of inflammatory disease.