Iron Sequestration by Magnesium Prussian Blue to Ameliorate Osteoarthritis Through Restoration of HIF‐1α Signaling and Ferroptosis Inhibition

ABSTRACT Osteoarthritis (OA) is a degenerative joint disorder driven by complex interactions among mechanical stress, inflammation, and metabolic dysregulation. Current clinical treatments remain unsatisfactory due to efficacy and safety concerns, and key pathological mechanisms have been less explored. From the histological and biochemical inspections of clinical samples from OA patients, we observed that hypoxia disruption and chondrocyte ferroptosis play significant roles in OA progression, raising the therapeutic demands for HIF‐1α stabilization and ferroptosis inhibition. Here, we developed a magnesium‐enriched Prussian blue nanomedicine (MgPB) that could effectively sequester ferrous overload to maintain HIF‐1α and inhibit chondrocyte ferroptosis. This study highlights that ferroptosis and HIF‐1α degradation form a self‐amplifying vicious cycle during OA progression. Our dual‐targeting strategy using MgPB concurrently achieves ferroptosis inhibition and restoration of HIF‐1α signaling, effectively breaking this pathological cycle, mitigating cartilage degeneration, and reprogramming the synovial microenvironment toward an anti‐inflammatory phenotype. These findings provide meaningful mechanistic insights into OA pathogenesis, thus offering a promising and effective treatment approach for OA.