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

Background and objectives: 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. Methods and results: Considering the powerful editability of tetrahedral framework nucleic acids (tFNAs) for gene delivery, we engineered a novel nanoscale gene delivery system using tetrahedral framework nucleic acids functionalized with miR-143-3p (tFNAs-143). Through comprehensive in vivo modeling of TMJOA destabilization and in vitro simulation of IL-1ß-induced inflammatory microenvironments, we systematically investigated the therapeutic efficacy and molecular mechanisms underlying OA pathophysiology of tFNAs-143. Our results demonstrated that tFNAs-143 exhibited excellent cellular internalization in chondrocytes and effectively mitigated TMJOA progression by impeding ferritinophagy-mediated ferroptosis. Conclusions: This study advanced miRNA delivery technology for TMJOA therapy, deepened the insights into TMJOA pathogenesis, and proposed a promising nano therapeutic strategy for developing targeted TMJOA therapies. Overall design: RNA-seq profiling of chondrocytes with or without treatment of IL-1ß, tFNAs-143 for 24 hours.