Natural-Sourced Nanocomplex Scavenging ROS and Inhibiting Inflammation by On-demand Drug Release for the Treatment of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease triggered by multiple factors, with a vicious cycle of “inflammation-oxidative stress-exacerbated inflammation”. The use of conventional RA drugs is limited due to poor efficiency or side effect. Effective and rational treatment of RA remains a significant challenge. Based on traditional Chinese medicine experience and recent pharmacology study, it is essential to simultaneously inhibit immune-inflammatory responses and remodel the RA microenvironment. In this regard, this study developed a “carrier-free” nanocomplex (Cel@PFA NP) composed of natural-sourced celastrol (Cel) and natural-derived poly(ferulic acid) (PFA) to treat RA. PFA not only act as drug carrier, but also can exert antioxidant effect (T-AOC of 20 mg/mL PFA NP: 0.64 ± 0.02 mM). By encapsulation, Cel@PFA NP improves Cel water solubility and reduces Cel toxicity. In addition, PFA can be degraded by enzyme in the RA microenvironment, on-demand releasing Cel and ferulic acid, exerting stronger antioxidant effects to restore endothelial dysfunction and inhibiting inflammatory cells, synergistically impeding RA progression. This study provides a novel approach for the application of natural active compounds with certain toxicity, offers new directions for the development of nanocarriers, and presents a new strategy for multi-target synergistic treatment of RA.