Carrier-free poly(glycyrrhetinic acid)-facilitated celastrol-loaded nanoparticle for high-efficiency low-toxicity treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a complex autoimmune disease associated with synovial inflammation and articular cartilage destruction. Currently, high-efficiency low-toxicity management of this intractable disease is highly urgent. Here, a drug-backboned polymer, polyglycyrrhetinic acid (PGA), was synthesized through the condensation of GA, a principal anti-inflammatory component of Glycyrrhiza glabra. PGA was then used as a therapeutic polyprodrug carrier to fabricate carrier-free PGA@Cel nanoparticles (NPs) for treating rheumatoid arthritis. The as-prepared NPs exhibited a uniformly spherical morphology with an average particle size of approximately 180 nm and a celastrol (Cel) loading capacity of around 4.5 %. Upon intravenous injection, the NPs demonstrated prolonged blood circulation, efficient accumulation at inflammatory joints through extravasation via leaky vasculature and subsequent inflammatory cell-mediated sequestration (ELVIS) effect. The present study demonstrated enhanced anti-inflammatory and rheumatic decay efficiency in rat models of antigen-induced arthritis, while simultaneously minimizing off-target toxicity. Overall, our results elucidate that this carrier-free drug-backboned nanopolydrug platform provides a promising strategy for RA therapy.