DNA-Grafted Hyaluronic Acid System with Enhanced Injectability and Biostability for Photo-Controlled Osteoarthritis Gene Therapy.
DNA-Grafted Hyaluronic Acid System with Enhanced Injectability and Biostability for Photo-Controlled Osteoarthritis Gene Therapy.
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DOI：
10.1002/advs.202004793
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Cui W
中科院分区：
文献类型：
--
作者：
Chen Z;Zhang F;Zhang H;Cheng L;Chen K;Shen J;Qi J;Deng L;He C;Santos HA;Cui W
基因治疗被认为是克服传统治疗方法局限性、取得满意效果的有力策略。然而，与剂型、给药方法，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化。本研究将干扰寡核苷酸与Au纳米棒结合，制备球形核酸（spherical nucleic acids，SNA），以调节骨关节炎（osteoarthritis，OA）中软骨炎症和退变相关的IL-1β mRNA异常表达，提高SNA的稳定性和细胞内化效率。此外，互补寡核苷酸被接枝到透明质酸（HA）上以获得DNA接枝的HA（DNAHA），用于通过碱基配对递送SNA，从而显著改善系统的可注射性和生物稳定性。加载SNA后，构建的DNAHA-SNA系统（HA-SNA）通过光热诱导的DNA去杂交和随后的后NIR原位杂交进行可逆的NIR触发的SNA按需释放。体外和体内实验表明，该系统在长时间内下调软骨中的分解代谢蛋白酶和上调合成代谢组分，以保护软骨细胞免受退行性变化并阻止OA的持续进展。构建了一种近红外光触发的热辅助基因治疗系统，以保护软骨细胞免受退行性变化，并阻止骨关节炎（OA）的持续发展。将干扰寡核苷酸与Au纳米棒整合以构建球形核酸，以提高稳定性和细胞内化效率，从而调节OA中软骨炎症和退行性变相关的异常IL-1β mRNA表达。
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. A NIR light‐triggered thermal‐assisted gene therapy system is constructed to safeguard the chondrocytes against degenerative changes and impede the continual advancement of osteoarthritis (OA). The interference oligonucleotides with the Au nanorods to fabricate the spherical nucleic acids is integrated to promote the stability and cell internalization efficiency, which regulated the cartilage inflammation and degeneration related abnormal IL‐1β mRNA expression in OA.
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