Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis

Jia-Lin Huang, Gan Jiang, Qing-Xiang Song, Xiao Gu, Meng Hu, Xiao-Lin Wang, Hua-Hua Song, Le-Pei Chen, Ying-Ying Lin, Di Jiang, Jun Chen, Jun-Feng Feng, Yong-Ming Qiu, Ji-Yao Jiang, Xin-Guo Jiang, Hong-Zhuan Chen () and Xiao-Ling Gao ()
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Jia-Lin Huang: Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine
Gan Jiang: Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine
Qing-Xiang Song: Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine
Xiao Gu: Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine
Meng Hu: Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine
Xiao-Lin Wang: Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine
Hua-Hua Song: Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine
Le-Pei Chen: Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine
Ying-Ying Lin: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Di Jiang: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University
Jun Chen: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University
Jun-Feng Feng: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Yong-Ming Qiu: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Ji-Yao Jiang: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Xin-Guo Jiang: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University
Hong-Zhuan Chen: Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine
Xiao-Ling Gao: Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: Abstract Hyperactivated Ras regulates many oncogenic pathways in several malignant human cancers including glioblastoma and it is an attractive target for cancer therapies. Ras activation in cancer cells drives protein internalization via macropinocytosis as a key nutrient-gaining process. By utilizing this unique endocytosis pathway, here we create a biologically inspired nanostructure that can induce cancer cells to ‘drink drugs’ for targeting activating transcription factor-5 (ATF5), an overexpressed anti-apoptotic transcription factor in glioblastoma. Apolipoprotein E3-reconstituted high-density lipoprotein is used to encapsulate the siRNA-loaded calcium phosphate core and facilitate it to penetrate the blood–brain barrier, thus targeting the glioblastoma cells in a macropinocytosis-dependent manner. The nanostructure carrying ATF5 siRNA exerts remarkable RNA-interfering efficiency, increases glioblastoma cell apoptosis and inhibits tumour cell growth both in vitro and in xenograft tumour models. This strategy of targeting the macropinocytosis caused by Ras activation provides a nanoparticle-based approach for precision therapy in glioblastoma and other Ras-activated cancers.

Date: 2017
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DOI: 10.1038/ncomms15144

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