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Chain-shattering Pt(IV)-backboned polymeric nanoplatform for efficient CRISPR/Cas9 gene editing to enhance 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
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Journal Article
Chain-shattering Pt(IV)-backboned polymeric nanoplatform for efficient CRISPR/Cas9 gene editing to enhance synergistic cancer therapy
2021
Overview
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 (NP
CSPt/pEZH2
) and synergistic treatment of prostate cancer. The pEZH2/Pt(II) could be effectively triggered to unpack/release from NP
CSPt/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.
Publisher
Tsinghua University Press
Subject
