Stepwise-targeting and hypoxia-responsive liposome AMVY@NPs carrying siYAP and verteporfin for glioblastoma therapy

  • J Nanobiotechnology. 2024 Aug 20;22(1):495. doi: 10.1186/s12951-024-02776-y.
Ji Qi  #  1  2 ,  Long Zhang  #  1  2 ,  Zhongyu Ren  1  2 ,  Yi Yuan  1  2 ,  Jiahao Yu  1  2 ,  Yining Zhang  1  2 ,  Linbo Gu  1  2 ,  Xu Wang  1  3 ,  Yan Wang  1  3 ,  Haoyue Xu  1  3 ,  Rutong Yu  1  3 ,  Xiuping Zhou  4  5
Affiliations
  • 1. Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, China.
  • 2. The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 3. Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
  • 4. Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, China. [email protected].
  • 5. Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. [email protected].
  • # Contributed equally.
PMID: 39164753 DOI: 10.1186/s12951-024-02776-y
Abstract

Background: 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.

Results: 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.

Conclusion: 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.

Keywords
Glioblastoma; Nanomedicine; Polymetronidazole; VP; siYAP.
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