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.

CRISPR / Cas9系统已成为一种有前途的癌症治疗基因编辑工具。然而，开发一种简单有效的纳米载体以结合CRISPR / Cas9系统和化学治疗药物以同时解决病毒载体的生物安全性和包装能力以及结合基因编辑化学疗法进行癌症治疗仍然是挑战。在本文中，开发了链断裂Pt（IV）结合的聚合物纳米平台，用于递送靶向EZH2的CRISPR / Cas9系统（NP _{CSPt / pEZH2}）和协同治疗前列腺癌。在癌细胞中，pEZH2 / Pt（II）可以有效地触发以链断裂的方式从NP _{CSPt / pEZH2}中解包/释放。体外PC-3细胞的EZH2基因破坏效率可达到32.2％和21.3％的体内肿瘤组织，导致有效抑制EZH2蛋白表达。此外，EZH2抑制后，H3K27me3可能会显着下调，从而导致染色质结构更为宽松，从而增加了释放的Pt（II）进入核DNA的通路，从而增强了细胞凋亡。两者合计，可以实现对前列腺癌细胞的实质性增殖抑制以及针对皮下异种移植肿瘤的进一步的85.4％生长抑制。这种链断裂的Pt（IV）结合的聚合物纳米平台系统不仅为CRISPR / Cas9系统提供了前瞻性的纳米载体，而且还拓宽了基因编辑-化学协同癌症治疗相结合的潜力。