Tetrahedral framework nucleic acids loaded with microRNA-17 for treating temporomandibular joint osteoarthritis: mechanisms of action.

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative joint disease involving cartilage degeneration, synovial inflammation, and subchondral bone remodeling. Current treatments are primarily palliative, lacking precise therapies. MicroRNA-based gene therapy is promising, but free miRNAs are limited by rapid degradation and poor cellular uptake. Given its marked downregulation in osteoarthritic chondrocytes and its multi-target capacity to concurrently suppress multiple matrix-degrading enzymes and inflammatory mediators, miR17 was selected as the therapeutic payload. Tetrahedral framework nucleic acids (tFNAs) offer high stability, efficient cellular uptake, and intrinsic anti-inflammatory activity, making them ideal miRNA carriers. In this study, TM17 was developed by loading miR17 onto tFNAs. Physicochemical characterization confirmed its stable structure and uniform size. In IL-1β-treated rat TMJ chondrocytes, TM17 was efficiently internalized, enhancing proliferation and migration, suppressing ROS generation and apoptosis while downregulating inflammatory factors (iNOS, MMP3, MMP13, ADAMTS5) and upregulating cartilage synthesis genes (COL2a1, ACAN, SOX9), restoring metabolic homeostasis. Mechanistically, TM17 inhibited p38 MAPK/NF-κB signaling and regulated the PTEN/AKT/HIF1α axis to reduce excessive HIF-1α activation, achieving dual anti-inflammatory and pro-synthetic effects. This first combination of tFNAs with miR17 demonstrates TM17 as a multifunctional nanodrug with efficient delivery and multitarget regulation, offering a potential strategy for TMJOA therapy.