Therapy of rheumatoid arthritis by reactive oxygen species-responsive celastrol-loaded nanomedicines via targeting macrophages apoptosis

Abstract

Inflammatory cascade is a prevalent and lethal adverse event that severely affects rheumatoid arthritis (RA) patients receiving clinic therapeutics. It is correlated with the response to macrophages caused by reactive oxygen species (ROS). Currently, ROS-targeted treatment is a potential strategy that can reduce the risk of RA-related obvious adverse effects, but at the cost of therapeutic efficacy. Herein, we reported folic acid (FA) modified ROS-responsive celastrol (Cel)-loaded (Cel/FA-Oxi-βCD NPs) that can release RA symptoms without chemotherapeutic agents and validated anti-inflammatory effect. In vitro study, NPs can be effectively internalized by activated macrophages and the released Cel from NPs significantly induced apoptosis in activated RAW264.7, indicating that Cel/FA-Oxi-βCD NPs remodeled the macrophages polarization homeostasis for the protection of inflamed joint microenvironment. Moreover, Cel/FA-Oxi-βCD NPs significantly decreased proinflammatory cytokines levels in serum, synovial and cartilage in collagen-induced arthritis (CIA) rats, and alleviated synovitis and cartilage destruction with excellent biocompatibility. Collectively, Cel/FA-Oxi-βCD NPs incorporated with ROS-responsive pro-apoptotic activity in macrophages, hold a great potential for clinical treatment of RA.