Upadacitinib and shikonin co-loaded nanodrug for rheumatoid arthritis therapy via attenuating inflammation and protecting cartilage.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation, excessive oxidative stress, and progressive joint destruction. Although upadacitinib (UP) monotherapy exhibits robust anti-inflammatory efficacy, its systemic administration is limited by a narrow target profile and hepatotoxicity. To address these challenges, we rationally designed a biomimetic nanodrug (HA-M@SHK-Fe@BSA-UP NPs) co-delivering UP with shikonin (SHK), a natural naphthoquinone with antioxidant activity and hepatoprotective effects. This nanoplatform self-assembled via iron-mediated metal-phenolic coordination, using bovine serum albumin (BSA) as a bridge, with a dual-surface modification of erythrocyte/macrophage hybrid membrane (M) and hyaluronic acid (HA). This architecture enabled prolonged circulation and pH-responsive drug release. In vitro, the nanodrug exhibited efficient reactive oxygen species (ROS) scavenging and targeted cellular uptake. Mechanistically, the nanodrug acted on macrophages and primary rat knee-joint chondrocytes (PRKCs) in parallel. It effectively drove M1-to-M2 polarization at least in part through the JAK1/STAT3/PKM2 axis and directly restored the function of PRKCs to suppress matrix degradation. In vivo, Ce6-based fluorescence imaging showed that the nanodrug accumulated 4.55-fold more in arthritic joints than free Ce6. Moreover, this nanodrug significantly suppressed inflammation at a low dosage and promoted cartilage and bone repair in AIA and CIA rat models, while showing reduced signs of liver injury. In summary, this self-assembled nanodrug offers a promising strategy for inflammatory disease treatment.