Polydatin and chitosan-silver co-loaded nanocomplexes for synergistic treatment of rheumatoid arthritis via repolarizing macrophages and inducing apoptosis of fibroblast-like synoviocytes

Schematic preparation of HA-M@PB@Ag@PD NPs and its performance in the treatment of rheumatoid arthritis. • HA-M@PB@Ag@PD NPs were developed for effective treatment of rheumatoid arthritis, in which polydatin and chitosan-silver were successfully loaded onto prussian blue nanoparticles. • HA-M@PB@Ag@PD NPs synergistically promoted the repolarization of inflammatory macrophages and induced apoptosis of RA fibroblast-like synoviocytes in vitro . • HA-M@PB@Ag@PD NPs exhibited significantly prolonged circulation time and accumulation in the arthritic joints in vivo. • HA-M@PB@Ag@PD NPs demonstrated pronounced anti-arthritic effects and significantly improved the synovial microenvironment of arthritic rats. Rheumatoid arthritis (RA) is a chronic and refractory autoimmune disease that primarily affects the synovium of diarthrodial joints. Inflammatory macrophages and fibroblast-like synoviocytes (FLS) in the synovial microenvironment produce pathogenic mediators such as cytokines and proteases that perpetuate immune-mediated inflammation and contribute to the destruction of cartilage and bone. Polydatin (PD), a natural active compound, has demonstrated potential anti-inflammatory and anti-arthritic effects. However, drug development and delivery of PD is still a great challenge owing to its low solubility, short half-life, and high dose requirement. In order to overcome these drawbacks, we developed a novel nanodrug system named HA-M@PB@Ag@PD NPs. This system is composed of hybrid membrane (M), hyaluronic acid (HA), Prussian blue nanoparticles (PB NPs), PD, and chitosan-silver (Chi-Ag). In vitro experiments demonstrated that HA-M@PB@Ag@PD NPs effectively cleared ROS, promoted the repolarization of inflammatory macrophages, and induced apoptosis of RA-FLS. Using a rat model of RA, HA-M@PB@Ag@PD NPs markedly suppressed joint inflammation, inhibited synovial hyperplasia, and protected joints against destruction of cartilage and bone. Moreover, HA-M@PB@Ag@PD NPs significantly improved the synovial microenvironment of arthritic rats by reducing the number of RA-FLS and inflammatory macrophages, and facilitating the repolarization of inflammatory macrophages.