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Research Article

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( ), Yubin Huang1,2( )
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
University of Science and Technology of China, Hefei 230026, China
Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
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Graphical Abstract

Abstract

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.

Keywords

CRISPR/Cas9gene editingEZH2Pt(IV)-backboned polymeric nanoplatformcombination therapy

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Nano Research
Volume 14 Issue 3,
March 2021
Pages 601-610
DOI: 10.1007/s12274-020-3066-4
Cite this article:
Zhang Q, Kuang G, He S, et al. Chain-shattering Pt(IV)-backboned polymeric nanoplatform for efficient CRISPR/Cas9 gene editing to enhance synergistic cancer therapy. Nano Research, 2021, 14(3): 601-610. https://doi.org/10.1007/s12274-020-3066-4
Topics:
Cell death Controlled drug deliveryDiseasesGenesOncologyTargeted drug deliveryTumorsUrology

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Received: 08 July 2020
Revised: 12 August 2020
Accepted: 22 August 2020
Published: 01 March 2021
© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature
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