Xu Liangliang, Liu Xiangzhong, Chen Jian, Xu Liwei, Yang Aofei, Li Zhanghua
Tongren Hospital Affiliated to Wuhan University, Wuhan, Hubei 430000, China.
The First hospital of Nanchang, Nanchang, Jiangxi 330000, China.
ACS Omega. 2025 Mar 4;10(10):10633-10641. doi: 10.1021/acsomega.4c11505. eCollection 2025 Mar 18.
Locked nucleic acid (LNA)-modified anti-microRNAs have been demonstrated to target mesenchymal stem cells (MSCs) to treat bone diseases. However, the "off-target" effect limits its clinical application.
We selected specific aptamer M4 of MSCs and employed the three-way junction (3WJ) as the core scaffold to construct nanoparticles (3WJ-M4-LNA) for specific delivery of anti-miRNA 138.
Our results suggested that the 3WJ-M4-LNA nanoparticles, not 3WJ-M4 or 3WJ-LNA, can specifically deliver anti-miRNA to MSCs, resulting in significant inhibition of miRNA 138 expression. Our experiment further confirmed that the nanoparticles can promote MSCs' osteogenic differentiation by activating the ERK1/2 pathway. In vivo, the nanoparticles promoted bone formation and improved the bone microarchitecture in rabbit osteoporosis models.
These results indicate that the 3WJ nanoparticles could develop as a specific therapeutic strategy for osteoporosis.
已证实锁核酸（LNA）修饰的抗微小RNA可靶向间充质干细胞（MSC）用于治疗骨疾病。然而，“脱靶”效应限制了其临床应用。
我们选择了MSC的特异性适配体M4，并采用三向接头（3WJ）作为核心支架构建纳米颗粒（3WJ-M4-LNA），用于抗微小RNA 138的特异性递送。
我们的结果表明，3WJ-M4-LNA纳米颗粒而非3WJ-M4或3WJ-LNA能够将抗微小RNA特异性递送至MSC，从而显著抑制微小RNA 138的表达。我们的实验进一步证实，这些纳米颗粒可通过激活ERK1/2途径促进MSC的成骨分化。在体内，这些纳米颗粒在兔骨质疏松模型中促进了骨形成并改善了骨微结构。
这些结果表明，3WJ纳米颗粒可发展成为一种治疗骨质疏松症的特异性治疗策略。
