Nano MiRNA-Functionating Tetrahedral Framework Nucleic Acid for Cartilage-Targeted Ferritinophagy Modulation to Attenuate Temporomandibular Joint Osteoarthritis.

Current clinical interventions lack effective strategies to arrest temporomandibular joint osteoarthritis (TMJOA) progression. Emerging evidence highlights the therapeutic potential of microRNAs (miRNAs) in osteoarthritis (OA) management, though critical challenges persist regarding delivery efficiency, including unsatisfactory cellular uptake, immunogenicity, and structural instability of miRNA-based therapeutics. Considering the powerful editability of tetrahedral framework nucleic acids (tFNAs) for gene delivery, a novel nanoscale gene delivery system using tetrahedral framework nucleic acids functionalized with miR-143-3p (tFNAs-143) is engineered. Through comprehensive in vivo modeling of TMJOA destabilization and in vitro simulation of IL-1β-induced inflammatory microenvironments, the therapeutic efficacy and molecular mechanisms underlying OA pathophysiology of tFNAs-143 are systematically investigated. The results demonstrate that tFNAs-143 exhibits excellent cellular internalization in chondrocytes and effectively mitigates TMJOA progression by impeding ferritinophagy-mediated ferroptosis. This study advances miRNA delivery technology for TMJOA therapy, deepens the insights into TMJOA pathogenesis, and proposes a promising nanotherapeutic strategy for developing targeted TMJOA therapies.