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，中期因子 (MDK) 上调限制了替莫唑胺 (TMZ) 带来的生存获益。 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，将这些生物制剂输送到 GBM 组织具有挑战性。在这里，我们展示了一种聚合物锁定融合脂质体 (Plofsome)，它可以穿过血脑屏障 (BBB)，并将短干扰 RNA 或 CRISPR-Cas9 核糖核蛋白复合物递送到 GBM 细胞的细胞质中。 Plofsome 的设计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，以便仅在穿过 BBB 并进入具有高 ROS 水平的 GBM 组织后才发生融合。我们的结果表明，在原位脑肿瘤模型中，Plofsomes 抑制 MDK 显着降低 TMZ 耐药性并抑制 GBM 生长。重要的是，Plofsomes 仅在肿瘤部位有效，而在正常组织中无效，这提高了 RNAi 和 CRISPR-Cas9 联合疗法的安全性。