The department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
Department of Spine Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Ann Rheum Dis. 2021 Mar;80(3):356-366. doi: 10.1136/annrheumdis-2020-218469. Epub 2020 Oct 27.
Despite preclinical studies involving miRNA therapeutics conducted in osteoarthritis (OA) over the years, none of these miRNAs have yet translated to clinical applications, owing largely to the lack of efficient intra-articular (IA) delivery systems. Here, we investigated therapeutic efficacy of the chondrocyte-specific aptamer-decorated PEGylated polyamidoamine nanoparticles (NPs)-based miRNAs delivery for OA.
The role of miR-141/200c cluster during skeletal and OA development was examined by miR-141/200c mice and Col2a1-CreER; miR-141/200c mice. Histological analysis was performed in mouse joints and human cartilage specimens. Chondrocyte-specific aptamer-decorated NPs was designed, and its penetration, stability and safety were evaluated. OA progression was assessed by micro-CT analysis, X-ray and Osteoarthritis Research Society International scores after destabilising the medial meniscus surgery with miR-141/200c manipulation by NPs IA injection. Mass spectrometry analysis, molecular docking and molecular dynamics simulations were performed to investigate the interaction between aptamer and receptor.
Increased retention of NPs inside joint space is observed. The NPs are freely and deeply penetrant to mice and human cartilage, and unexpectedly persist in chondrocytes for at least 5 weeks. OA chondrocytes microenviroment improves endo/lysosomal escape of microRNAs (miRNAs). Therapeutically, IA injection of miR-141/200c inhibitors provides strong chondroprotection, whereas ectopic expression of miR-141/200c exacerbates OA. Mechanistically, miR-141/200c promotes OA by targeting SIRT1, which acetylates histone in the promoters of interleukin 6 (IL-6), thereby activating IL-6/STAT3 pathway.
Our findings indicate that this nanocarrier can optimise the transport kinetics of miR-141/200c into chondrocytes, fostering miRNA-specific disease-modifying OA drugs development.
尽管多年来在骨关节炎（OA）中进行了涉及 miRNA 治疗的临床前研究，但由于缺乏有效的关节内（IA）递药系统，这些 miRNA 均尚未转化为临床应用。在此，我们研究了基于软骨细胞特异性适体修饰的聚乙二醇化聚酰胺胺纳米颗粒（NPs）的 miRNA 递药系统在 OA 中的治疗效果。
通过 miR-141/200c 小鼠和 Col2a1-CreER；miR-141/200c 小鼠来研究 miR-141/200c 簇在骨骼和 OA 发育过程中的作用。在小鼠关节和人软骨标本中进行组织学分析。设计了软骨细胞特异性适体修饰的 NPs，并对其穿透性、稳定性和安全性进行了评估。通过 micro-CT 分析、X 射线和骨关节炎研究协会国际评分评估 OA 进展，然后通过 NPsIA 注射来破坏内侧半月板手术，从而操纵 miR-141/200c。进行质谱分析、分子对接和分子动力学模拟，以研究适体与受体之间的相互作用。
观察到 NPs 在关节腔内的滞留增加。NPs 可自由且深入地穿透到小鼠和人软骨中，出人意料的是，至少在软骨细胞中可稳定存在 5 周。OA 软骨细胞微环境可改善 miRNA（miRNAs）的内体/溶酶体逃逸。IA 注射 miR-141/200c 抑制剂可提供强大的软骨保护作用，而异位表达 miR-141/200c 则加剧 OA。机制上，miR-141/200c 通过靶向 SIRT1 促进 OA，SIRT1 乙酰化组蛋白在白细胞介素 6（IL-6）启动子中，从而激活 IL-6/STAT3 通路。
我们的研究结果表明，这种纳米载体可以优化 miR-141/200c 进入软骨细胞的运输动力学，促进针对特定 miRNA 的治疗性 OA 药物的开发。
