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Brain-targeted CRISPR/Cas9 nanomedicine for effective glioblastoma therapy  

Weimin Ruan#, Mingzhu Jiao#, Sen Xu#, Muhammad Ismail, Xuan Xie, Yang An, Haixing Guo, Rongjun Qian*, Bingyang Shi*, Meng Zheng*  

Journal of Controlled Release 2022, 351, 739–751 (IF=11.467)

Abstract

CRISPR/Cas9 gene-editing technology shows great potential for treating a variety of diseases, such as glioblastoma multiforme (GBM). However, CRISPR components suffer from inherent delivery challenges, such as poor in vivo stability of Cas9 protein and gRNA, low blood-brain barrier (BBB) permeability and non-specific tissue or cell targeting. These defects have limited the application of Cas9/gRNA ribonucleoprotein (RNP) complexes for GBM therapy. Here, we developed a brain-targeted CRISPR/Cas9 based nanomedicine by fabricating an angiopep-2 decorated, guanidinium and fluorine functionalized polymeric nanoparticle with loading Cas9/gRNA RNP for the treatment of GBM. The guanidinium and fluorine domains of our polymeric nanoparticles were both capable of interacting with Cas9/gRNA RNP to stabilize it in blood circulation, without impairing its activity. Moreover, by leveraging angiopep-2 peptide functionality, the RNP nanoparticles efficiently crossed the BBB and accumulated in brain tumors. In U87MG cells, we achieved approximately 32% gene knockout and 67% protein reduction in the targeted proto-oncogene polo-like kinase 1 (PLK1). This was sufficient to suppress tumor growth and significantly improved the median survival time of mice bearing orthotopic glioblastoma to 40 days, while inducing negligible side or off-target effects. These results suggest that the developed brain-targeted CRISPR/Cas9 based nanomedicine shows promise for effective human glioblastoma gene therapy.



 
? 2017 河南大学-麦考瑞大学
生物医学联合创新中心
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  地址
河南省开封市
河南大学金明校区,生命科学学院
475004
 技术支持:河南科加
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邮箱: jcbi@vip.henu.edu.cn
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