Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that frequently involves cartilage damage and the destruction of the bone structure, ultimately resulting in disability and long-term pain. It is clear that overexpression of reactive oxygen species (ROS) and the complex inflammatory microenvironment are the main causes of RA pathogenesis; thereby, the efficacy of any single-drug treatment is limited. Herein, we formulated a therapeutic hyaluronic acid derivative (PAM-HA) with adsorption capacity to the subchondral bone, a long retention time within inflamed joints, and ROS-scavenging capacity, which was used as a drug carrier for realizing the controlled release of sinomenine (Sin) within arthritic joints. This "drug in therapeutic polymer" design strategy was aimed at realizing antioxidant and anti-inflammatory combination therapy for RA. In vivo experiments suggest that PAM-HA@Sin NPs can be retained in the inflamed joints of rats for a long time compared with commercially available free Sin injections. As expected, therapeutic PAM-HA polymeric carriers can increase joint lubrication and reduce oxidative stress, while the released Sin induces downregulation of proinflammatory factors (TNF-α and IL-1β) and upregulation of anti-inflammatory factors (Arg-1 and IL-10) via the NF-κB pathway. In summary, a ROS-scavenging hyaluronic acid (HA) derivative was developed as the nanocarrier for Sin delivery to simultaneously remodel the oxidative/inflammatory microenvironment in RA, which opens up new horizons for the development of therapeutic polymers and the combined therapeutic strategies.
Keywords: intra-articular delivery; macrophages; reactive oxygen species; rheumatoid arthritis; sinomenine; therapeutic polymer.