Tetrahedral Framework Nucleic Acid-Based Cepharanthine Attenuates TMJOA via cGAS-STING-NF-κB Pathway Modulation and Macrophage Reprogramming.

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative joint disease characterized by cartilage degradation, subchondral bone remodeling, and chronic inflammation for which effective therapies remain lacking. In this study, we develop a cepharanthine-loaded tetrahedral framework nucleic acid nanoplatform (tFNA@Cep) and evaluate its physicochemical properties, biological performance, and therapeutic potential in TMJOA. The nanostructure exhibits excellent stability, favorable size distribution, and efficient cellular uptake, with preserved structural integrity under physiological conditions. In a murine model of TMJOA induced by unilateral anterior crossbite, tFNA@Cep treatment significantly improved cartilage thickness and subchondral bone architecture, accompanied by restored expression of Col II and RUNX2. Mechanistically, tFNA@Cep promotes macrophage polarization toward an anti-inflammatory M2 phenotype and suppresses activation of the cGAS-STING-NFκB pathway and intracellular ROS production. Moreover, the conditioned medium from tFNA@Cep-treated macrophages enhances anabolic gene expression in chondrocytes, indicating an immunomodulatory effect on cartilage regeneration. Collectively, these findings demonstrate that tFNA@Cep functions as a multifunctional nanotherapeutic agent capable of integrating drug delivery, inflammation resolution, and osteochondral repair, providing a promising strategy for the treatment of TMJOA and related joint disorders.