Nanozyme hydrogels remodel pathological microenvironment for temporomandibular joint osteoarthritis therapy via inhibiting MAPK signal pathway.

Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative disease that lacks effective treatment options. The inflammatory microenvironment caused by excessive reactive oxygen species (ROS) in TMJ-OA leads to chondrocyte apoptosis, extracellular matrix (ECM) degradation, and abnormal cartilage metabolism. Herein, we innovatively constructed a manganese-nitrogen-carbon single-atom nanozymes (Mn-NC SAzymes) - chitosan composite hydrogel system. A coordination structure of Mn-N(4) was proposed based on X-ray absorption fine structure spectra. The composite hydrogel achieves an integration of atomic level catalytic design and a localized delivery system. It fully leverages the synergistic dual enzyme-like activities of the Mn - NC SAzyme and the active repair properties of chitosan, successfully overcoming the limitations of traditional materials that target only a single site. It realizes a multi-dimensional functional synergy, ranging from efficient ROS scavenging and regulation of the inflammatory microenvironment to promoting combined bone-cartilage repair. Furthermore, through in-depth analysis of molecular mechanisms, the mechanism by which it inhibits inflammation-induced chondrocyte apoptosis and ECM degradation via suppression of the MAPK signaling pathway was elucidated. Density functional theory (DFT) was also employed to uncover the catalytic reaction pathways. This systematically explained the structure-property relationship of SAzymes and the mechanism of functional reconstruction in vivo, driving the transition of TMJ-OA treatment from mere symptom relief to multi-dimensional functional reconstruction.