Disulfide bond-based oxidation-responsive triptolide-loaded nanodrug for inflammation-targeted treatment of collagen-induced arthritis

M1 macrophages play a crucial role in the development of rheumatoid arthritis (RA), which can produce various inflammation cytokines, and reactive oxygen species (ROS). Disulfide bonds as reduction-responsive linkages have been extensively employed in the drug delivery systems. However, disulfide bonds are rarely reported in the development of the oxidation-responsive drug carriers. Herein, we designed and synthetized novel oxidation-responsive drug carriers based on disulfide bonds, and further developed nanoparticles (FA-TP@NPs) by self-assembly for the RA treatment. FA-TP@NPs was decorated with folic acid and loaded with triptolide (TP), a potent anti-inflammation Chinese medicine, to target and enter M1 macrophages through the folate receptor on the cytomembrane for simultaneous repolarization of the M2 macrophage and elimination of the M1 macrophage. As expected, FA-TP@NPs exhibited an oxidation-responsive TP release via disulfide-bond oxidation and ester-bond hydrolysis in the presence of intracellular ROS, which accumulated preferentially in inflamed joints. FA-TP@NPs exerted a potent anti-arthritic effect with high biosafety in CIA mice, as evidenced by repolarizing M2 macrophages, inducing M1 macrophage apoptosis, and reducing TNF-α, IL-6, and IL-1β expression. This work shows that FA-TP@NPs give a deep insight into disulfide bond-based oxidation-responsive drug delivery systems, and provide a potential platform for RA treatment.