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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\u2010based 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\u2010143\u20103p (tFNAs\u2010143) is engineered. Through comprehensive in\u2009vivo modeling of TMJOA destabilization and in\u2009vitro simulation of IL\u20101\u03b2\u2010induced inflammatory microenvironments, the therapeutic efficacy and molecular mechanisms underlying OA pathophysiology of tFNAs\u2010143 are systematically investigated. The results demonstrate that tFNAs\u2010143 exhibits excellent cellular internalization in chondrocytes and effectively mitigates TMJOA progression by impeding ferritinophagy\u2010mediated ferroptosis. 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