Zhao Yu, Qin Jie, Yu Daohan, Liu Yuxiang, Song Dan, Tian Kaifu, Chen Hao, Ye Qile, Wang Xinyu, Xu Tianye, Xuan Hanwen, Sun Nan, Ma Wenbin, Zhong Junzhe, Sun Penggang, Song Yu, Hu Jingze, Zhao Yunlei, Hou Xintong, Meng Xiangqi, Jiang Chuanlu, Cai Jinquan
Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
Nat Nanotechnol. 2024 Dec;19(12):1869-1879. doi: 10.1038/s41565-024-01769-0. Epub 2024 Aug 29.
In patients with glioblastoma (GBM), upregulated midkine (MDK) limits the survival benefits conferred by temozolomide (TMZ). RNA interference (RNAi) and CRISPR-Cas9 gene editing technology are attractive approaches for regulating MDK expression. However, delivering these biologics to GBM tissue is challenging. Here we demonstrate a polymer-locking fusogenic liposome (Plofsome) that can be transported across the blood-brain barrier (BBB) and deliver short interfering RNA or CRISPR-Cas9 ribonucleoprotein complexes into the cytoplasm of GBM cells. Plofsome is designed by integrating a 'lock' into the fusogenic liposome using a traceless reactive oxygen species (ROS)-cleavable linker so that fusion occurs only after crossing the BBB and entering the GBM tissue with high ROS levels. Our results showed that MDK suppression by Plofsomes significantly reduced TMZ resistance and inhibited GBM growth in orthotopic brain tumour models. Importantly, Plofsomes are effective only at tumour sites and not in normal tissues, which improves the safety of combined RNAi and CRISPR-Cas9 therapeutics.
在胶质母细胞瘤（GBM）患者中，上调的中期因子（MDK）会限制替莫唑胺（TMZ）带来的生存益处。RNA干扰（RNAi）和CRISPR-Cas9基因编辑技术是调节MDK表达的有吸引力的方法。然而，将这些生物制剂递送至GBM组织具有挑战性。在此，我们展示了一种聚合物锁定融合脂质体（Plofsome），其能够穿过血脑屏障（BBB），并将短干扰RNA或CRISPR-Cas9核糖核蛋白复合物递送至GBM细胞的细胞质中。Plofsome是通过使用无痕活性氧（ROS）可裂解接头将“锁”整合到融合脂质体中而设计的，这样融合仅在穿过BBB并进入具有高ROS水平的GBM组织后才会发生。我们的结果表明，Plofsome对MDK的抑制作用显著降低了原位脑肿瘤模型中的TMZ耐药性并抑制了GBM的生长。重要的是，Plofsome仅在肿瘤部位有效，而在正常组织中无效，这提高了联合RNAi和CRISPR-Cas9疗法的安全性。
