Shi Yongxiang, Shen Shuying, Huang Dongdong, Yilamu Kamuran, Chen Zhengju, Wang Kefan, Chen Pengyu, Pan Nan, Jin Zhanping, Guo Lei, Xu Wenbin, Zhao Xing
Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City 310009, Zhejiang Province, China.
Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City 310009, Zhejiang Province, China; Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou City 310016, China; Key Laboratory of Mechanism Research and Precision Repair of Orthopedic Trauma and Aging Diseases of Zhejiang Province, Zhejiang 310016, China.
J Control Release. 2025 Feb 10;378:294-305. doi: 10.1016/j.jconrel.2024.12.019. Epub 2024 Dec 17.
Osteoarthritis (OA) is a chronic joint disease characterized by the progressive degradation of articular cartilage. Delivering functional genes to chondrocytes to modulate the inflammatory environment offers a promising approach to treating OA. However, the dense extracellular matrix (ECM) in the OA microenvironment and the rapid clearance of naked nucleic acids from synovial fluid present significant challenges. Here we report the development of highly branched poly(β-amino ester)s (HPAEs) for effective delivery of F-box protein 6 (FBXO6) gene to treat OA. Four HPAEs were synthesized using an "A2 + B4 + C2" Michael addition strategy. By optimizing the chemical compositions and topological structures, the optimal HMDA-2 was identified to exhibit superior transfection efficiency, outperforming the commercial reagents Lipofectamine 3000 and branched polyethyleneimine (PEI). HMDA-2 was further employed to deliver FBXO6 plasmid to effectively regulate HO expression, improve oxidative stress injury, and reduce the expression of MMP-13 and COX-2 in chondrocytes, leading to significant reductions in synovial inflammatory cell infiltration, cartilage loss, and bone erosion. After intra-articular injection in an anterior cruciate ligament transection (ACLT) rat model, HMDA-2/FBXO6 polyplexes substantially reduced synovitis and cartilage damage, improved cartilage surface integrity, and restored proteoglycan levels. The delivery of FBXO6 with HMDA-2 to chondrocytes offers a potential treatment for OA.
骨关节炎（OA）是一种慢性关节疾病，其特征是关节软骨进行性退化。将功能基因传递给软骨细胞以调节炎症环境为治疗OA提供了一种有前景的方法。然而，OA微环境中致密的细胞外基质（ECM）以及滑液中裸核酸的快速清除带来了重大挑战。在此，我们报告了用于有效递送F-box蛋白6（FBXO6）基因以治疗OA的高度支化聚（β-氨基酯）（HPAEs）的开发。使用“A2 + B4 + C2”迈克尔加成策略合成了四种HPAEs。通过优化化学组成和拓扑结构，确定了最佳的HMDA-2，其表现出优异的转染效率，优于商业试剂Lipofectamine 3000和支化聚乙烯亚胺（PEI）。HMDA-2进一步用于递送FBXO6质粒，以有效调节HO表达，改善氧化应激损伤，并降低软骨细胞中MMP-13和COX-2的表达，从而导致滑膜炎症细胞浸润、软骨损失和骨侵蚀显著减少。在大鼠前交叉韧带横断（ACLT）模型中进行关节内注射后，HMDA-2/FBXO6多聚体显著减轻了滑膜炎和软骨损伤，改善了软骨表面完整性，并恢复了蛋白聚糖水平。用HMDA-2将FBXO6递送至软骨细胞为OA提供了一种潜在的治疗方法。
