Coordination of Oligonucleotides into Enzyme-Mimetic Nanostructures for Ameliorating Osteoarthritis through Intervening in Articular Cartilage and Subchondral Bone

Abstract Osteoarthritis (OA) is a common degenerative joint disease, characterized by oxidative stress, excessive inflammatory responses, cartilage matrix degradation, and subchondral bone loss. However, a therapeutic strategy that simultaneously addresses these interconnected pathologies remains elusive in current nanomedicine. In this study, we prepare a DNA nanostructure with antioxidant enzyme-mimetic activities through the coordination-driven co-assembly of oligonucleotides and inorganic cerium pyrophosphate crystals. After intra-articular injection, the valence transition property of cerium ions enables the nanoparticles to scavenge reactive oxygen species, thereby ameliorating oxidative stress-induced articular cartilage damage and facilitating cartilage extracellular matrix regeneration. Meanwhile, the adenosine-rich oligonucleotide induces M2 macrophage polarization, thereby alleviating inflammatory responses. Notably, the presence of pyrophosphate anions directly inhibits osteoclast activity, facilitating subchondral bone remodeling. This work demonstrates a universal coordination-driven strategy, which can be adopted to prepare other enzyme-mimetic nanoparticles through tailoring the components and structures for the targeted treatment of diseases beyond OA.