Targeted Combination of Antioxidative and Anti-Inflammatory Therapy of Rheumatoid Arthritis using Multifunctional...

Abundant reactive oxygen species and tumor necrosis factor-α (TNF-α) cytokine supply of M1-type macrophages boost rheumatoid arthritis (RA) pathological process. For efficient RA therapy, here a multifunctional nanoplatform is presented based on generation 5 (G5) poly(amidoamine) dendrimer-entrapped gold nanoparticles (Au DENPs) to achieve co-delivery of antioxidant alpha-tocopheryl succinate (α-TOS) and anti-inflammatory anti-TNF-α siRNA to macrophage cells. G5 dendrimers with amine termini are sequentially functionalized with 1,3-propane sultone (1,3-PS), α-TOS through a polyethylene glycol (PEG) spacer, and PEGylated folic acid (FA), and subsequently entrapped with Au NPs. The generated functional Au DENPs exhibit desired cytocompatibility, zwitterion-rendered antifouling property, and FA-mediated targeting specificity, enabling serum-enhanced siRNA delivery to M1-type macrophage cells. Meanwhile, the attached α-TOS affords enhanced oxidation resistance of macrophage cells. In vivo investigation shows that the treatment of a collagen-induced arthritis mouse model using α-TOS-modified Au DENPs/TNF-α siRNA polyplexes can achieve excellent combination therapy effect in inflammatory cytokines downregulation of RA lesion and bone erosions. The therapeutic efficacy is also supported by 3D micro-computed tomography analysis and TNF-α cytokine reduction of RA lesion joints in the mRNA, protein, and histology levels. The created multifunctional nanoplatform may be employed in antioxidative and anti-inflammatory combination therapy of RA.