Research Article

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2021, 14(3): 601–610

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https://doi.org/10.1007/s12274-020-3066-4

Chain-shattering Pt(IV)-backboned polymeric nanoplatform for efficient CRISPR/Cas9 gene editing to enhance synergistic cancer therapy

Qingfei Zhang1,2, Gaizhen Kuang3, Shasha He1 (✉), Sha Liu1,2, Hongtong Lu1,2, Xiaoyuan Li1, Dongfang Zhou1,4 (✉), and Yubin Huang1,2 (✉)

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1 State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
2 University of Science and Technology of China, Hefei 230026, China
3 Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China
4 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China

Keywords: CRISPR/Cas9, gene editing, EZH2, Pt(IV)-backboned polymeric nanoplatform, combination therapy
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  • Abstract
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CRISPR/Cas9 system has become a promising gene editing tool for cancer treatment. However, development of a simple and effective nanocarrier to incorporate CRISPR/Cas9 system and chemotherapeutic drugs to concurrently tackle the biological safety and packaging capacity of viral vectors and combine gene editing-chemo for cancer therapy still remains challenges. Herein, a chain-shattering Pt(IV)-backboned polymeric nanoplatform is developed for the delivery of EZH2-targeted CRISPR/Cas9 system (NPCSPt/pEZH2) and synergistic treatment of prostate cancer. The pEZH2/Pt(II) could be effectively triggered to unpack/release from NPCSPt/pEZH2 in a chain-shattering manner in cancer cells. The EZH2 gene disruption efficiency could be achieved up to 32.2% of PC-3 cells in vitro and 21.3% of tumor tissues in vivo, leading to effective suppression of EZH2 protein expression. Moreover, significant H3K27me3 downregulation could occur after EZH2 suppression, resulting in a more permissive chromatin structure that increases the accessibility of released Pt(II) to nuclear DNA for enhanced apoptosis. Taken together, substantial proliferation inhibition of prostate cancer cells and further 85.4% growth repression against subcutaneous xenograft tumor could be achieved. This chain-shattering Pt(IV)-backboned polymeric nanoplatform system not only provides a prospective nanocarrier for CRISPR/Cas9 system delivery, but also broadens the potential of combining gene editing-chemo synergistic cancer therapy.
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Chain-shattering Pt(IV)-backboned polymeric nanoplatform for efficient CRISPR/Cas9 gene editing to enhance synergistic cancer therapy. Nano Res. 2021, 14(3): 601–610 https://doi.org/10.1007/s12274-020-3066-4

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