Yueh Po-Fu, Chiang I-Tsang, Weng Yueh-Shan, Liu Yu-Chang, Wong Raymond C B, Chen Cheng-Yu, Hsu Justin Bo-Kai, Jeng Long-Bin, Shyu Woei-Cherng, Hsu Fei-Ting
Institute of Traditional Medicine, School of Medicine, National Yang Ming Chiao Tung University, 112, Taipei, Beitou, Taiwan (ROC).
Research assistant Center, Show Chwan Memorial Hospital, 500, Changhua, Taiwan (ROC).
J Exp Clin Cancer Res. 2025 Mar 25;44(1):107. doi: 10.1186/s13046-025-03336-4.
Addressing the challenges of identifying suitable targets and effective delivery strategies is critical in pursuing therapeutic solutions for glioblastoma (GBM). This study focuses on the therapeutic potential of microRNA-124 (miR-124), known for its tumor-suppressing properties, by investigating its ability to target key oncogenic pathways in GBM. The results reveal that CDK4 and CDK6-cyclin-dependent kinases that promote cell cycle progression-are significantly overexpressed in GBM brain samples, underscoring their role in tumor proliferation and identifying them as critical targets for miR-124 intervention. However, delivering miRNA-based therapies remains a major obstacle due to the instability of RNA molecules and the difficulty in achieving targeted, efficient delivery. To address these issues, this research introduces an innovative, non-viral dual-gene delivery platform that utilizes umbilical cord mesenchymal stem cells (UMSCs) and their exosomes to transport miR-124 and programmed cell death protein-1 (PD-1). The efficacy of this dual-gene delivery system was validated using an orthotopic GBM model, which closely mimics the tumor microenvironment seen in patients. Experimental results demonstrate that the UMSC/miR-124-PD-1 complex and its exosomes successfully induce apoptosis in GBM cells, significantly inhibiting tumor growth. Notably, these treatments show minimal cytotoxic effects on normal glial cells, highlighting their safety and selectivity. Moreover, the study highlights the immunomodulatory properties of UMSC/miR-124-PD-1 and its exosomes, enhancing the activation of immune cells such as T cells and dendritic cells, while reducing immunosuppressive cells populations like regulatory T cells and myeloid-derived suppressor cells. The orchestrated dual-gene delivery system by UMSCs and exosomes showcased targeted tumor inhibition and positive immune modulation, emphasizing its potential as a promising therapeutic approach for GBM.
应对识别合适靶点和有效递送策略的挑战对于寻求胶质母细胞瘤（GBM）的治疗方案至关重要。本研究聚焦于以其肿瘤抑制特性而闻名的微小RNA-124（miR-124）的治疗潜力，通过研究其靶向GBM中关键致癌途径的能力。结果显示，促进细胞周期进程的细胞周期蛋白依赖性激酶CDK4和CDK6在GBM脑样本中显著过表达，突出了它们在肿瘤增殖中的作用，并将它们确定为miR-124干预的关键靶点。然而，由于RNA分子的不稳定性以及实现靶向、高效递送的困难，基于miRNA的疗法的递送仍然是一个主要障碍。为了解决这些问题，本研究引入了一种创新的非病毒双基因递送平台，该平台利用脐带间充质干细胞（UMSC）及其外泌体来运输miR-124和程序性细胞死亡蛋白1（PD-1）。使用原位GBM模型验证了这种双基因递送系统的疗效，该模型紧密模拟了患者体内的肿瘤微环境。实验结果表明，UMSC/miR-124-PD-1复合物及其外泌体成功诱导GBM细胞凋亡，显著抑制肿瘤生长。值得注意的是，这些治疗对正常神经胶质细胞的细胞毒性作用极小，突出了它们的安全性和选择性。此外，该研究强调了UMSC/miR-124-PD-1及其外泌体的免疫调节特性，增强了T细胞和树突状细胞等免疫细胞的活化，同时减少了调节性T细胞和骨髓来源的抑制性细胞等免疫抑制细胞群体。UMSC和外泌体精心设计的双基因递送系统展示了靶向肿瘤抑制和积极的免疫调节作用，强调了其作为GBM一种有前景的治疗方法的潜力。
