Hippo通路是一条保守的肿瘤抑制信号通路，其失调通常与异常细胞生长和肿瘤发生有关。我们之前揭示了 Hippo 通路的关键效应子转录共激活因子 Yes 相关蛋白 (YAP) 是最常见的恶性脑肿瘤胶质母细胞瘤 (GBM) 的分子靶点。用小干扰RNA（siYAP）或特异性抑制剂维替泊芬（VP）抑制YAP可以在一定程度上抑制GBM生长。在本研究中，为了增强siYAP和VP的抗GBM作用，我们设计了逐步靶向和缺氧-响应性脂质体（AMVY@NPs），封装了缺氧响应性聚甲硝唑包被的VP和DOTAP吸附的siYAP，表面具有angiopep-2（A2）修饰。 AMVY@NPs 表现出优异的血脑屏障穿越、GBM 靶向性以及缺氧响应性和高效的 siYAP 和 VP 释放特性。通过抑制 YAP 的表达和功能，AMVY@NPs 在体外协同抑制 GBM 的生长和干性。此外，AMVY@NPs 强烈抑制原位 U87 异种移植物的生长，提高荷瘤小鼠的存活率，且没有副作用。携带 siYAP 和 VP 的逐步靶向和缺氧响应脂质体 AMVY@NPs 特异性靶向 YAP 有效抑制 GBM 进展。这项研究为未来 GBM 的分子靶向治疗提供了有价值的药物输送平台和创造性见解。© 2024。作者。

The Hippo pathway is a conserved tumour suppressor signalling pathway, and its dysregulation is often associated with abnormal cell growth and tumorigenesis. We previously revealed that the transcriptional coactivator Yes-associated protein (YAP), the key effector of the Hippo pathway, is a molecular target for glioblastoma (GBM), the most common malignant brain tumour. Inhibiting YAP with small interfering RNA (siYAP) or the specific inhibitor verteporfin (VP) can diminish GBM growth to a certain degree.In this study, to enhance the anti-GBM effect of siYAP and VP, we designed stepwise-targeting and hypoxia-responsive liposomes (AMVY@NPs), which encapsulate hypoxia-responsive polymetronidazole-coated VP and DOTAP adsorbed siYAP, with angiopep-2 (A2) modification on the surface. AMVY@NPs exhibited excellent blood‒brain barrier crossing, GBM targeting, and hypoxia-responsive and efficient siYAP and VP release properties. By inhibiting the expression and function of YAP, AMVY@NPs synergistically inhibited both the growth and stemness of GBM in vitro. Moreover, AMVY@NPs strongly inhibited the growth of orthotopic U87 xenografts and improved the survival of tumour-bearing mice without adverse effects.Specific targeting of YAP with stepwise-targeting and hypoxia-responsive liposome AMVY@NPs carrying siYAP and VP efficiently inhibited GBM progression. This study provides a valuable drug delivery platform and creative insights for molecular targeted treatment of GBM in the future.© 2024. The Author(s).