Gene therapy is identified as a powerful strategy to overcome the limitations of traditional therapeutics to achieve satisfactory effects. However, various challenges related to the dosage form, delivery method, and, especially, application value, hampered the clinical transition of gene therapy. Here, aiming to regulate the cartilage inflammation and degeneration related abnormal IL‐1β mRNA expression in osteoarthritis (OA), the interference oligonucleotides is integrated with the Au nanorods to fabricate the spherical nucleic acids (SNAs), to promote the stability and cell internalization efficiency. Furthermore, the complementary oligonucleotides are grafted onto hyaluronic acid (HA) to obtained DNA‐grafted HA (^DNAHA) for SNAs delivery by base pairing, resulting in significantly improved injectability and bio‐stability of the system. After loading SNAs, the constructed ^DNAHA‐SNAs system (HA‐SNAs) performs a reversible NIR‐triggered on‐demand release of SNAs by photo‐thermal induced DNA dehybridization and followed by post‐NIR in situ hybridization. The in vitro and in vivo experiments showed that this system down‐regulated catabolic proteases and up‐regulated anabolic components in cartilage over extended periods of time, to safeguard the chondrocytes against degenerative changes and impede the continual advancement of OA.

中文翻译：

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DNA 移植透明质酸系统具有增强的可注射性和生物稳定性，用于光控骨关节炎基因治疗

基因治疗被认为是克服传统疗法局限性以达到满意效果的有力策略。然而，与剂型、递送方法，特别是应用价值相关的各种挑战阻碍了基因治疗的临床转变。在此，旨在调节骨关节炎（OA）中与软骨炎症和退变相关的异常IL- 1βmRNA表达，将干扰寡核苷酸与金纳米棒整合以制造球形核酸（SNA），以促进稳定性和细胞内化效率。此外，将互补寡核苷酸嫁接到透明质酸（HA）上，获得DNA嫁接HA（^DNA HA），用于通过碱基配对进行SNA递送，从而显着提高系统的可注射性和生物稳定性。加载 SNA 后，构建的^DNA HA-SNA 系统 (HA-SNA) 通过光热诱导 DNA 去杂交，然后进行后近红外原位杂交，执行可逆近红外触发的 SNA 按需释放。体外和体内实验表明，该系统在较长时间内下调软骨中的分解代谢蛋白酶并上调软骨中的合成代谢成分，以保护软骨细胞免受退行性变化并阻碍 OA 的持续发展。