Functionalized Biomimetic Nanoparticles Targeting the IL-10/IL-10Rα/Glycolytic Axis in Synovial Macrophages Alleviate Cartilage Degeneration in Osteoarthritis.

Osteoarthritis (OA) is a low-grade inflammatory disease that is highly associated with severe hyperplasia of the synovial membrane and the degeneration of cartilage. Interleukin-10 (IL-10), has been extensively studied, while its receptor, IL-10Rα, has not been widely mentioned in the context of OA. A significant difference is found in the expression of IL-10Rα in synovial macrophages from normal and OA patients, along with a marked increase in the glycolytic activity of synovial macrophages. In IL-10Rα OA mice, the specific deficiency of IL-10Rα exacerbated the progression of OA. Mechanistically, hypoxia-inducible factor-1α (HIF-1α) is identified as a key transcription factor, and its inhibition significantly weakened the glycolytic process. Additionally, differences in ferroptosis of chondrocytes are observed. After co-culturing the two types of cells in vitro, a significant connection is found between the glycolytic state of synovial macrophages and the ferroptosis of chondrocytes. To achieve targeted therapy, MI@UN, a biomimetic nanoparticle encapsulating NO-prednisolone in UIO-66-NH, surface-modified with IL-10, and coated with macrophage membranes (MM), is developed. It significantly slows osteoarthritis progression in mice. This offers new insights into OA pathogenesis, highlighting IL-10Rα as a therapeutic target and supporting MI@UN's translational use for OA treatment.