School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong 511442, P. R. China.
National Engineering Research Center for Tissue Restoration and Reconstruction and Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou, Guangdong 510006, P. R. China.
ACS Nano. 2022 Sep 27;16(9):13821-13833. doi: 10.1021/acsnano.2c01885. Epub 2022 Aug 22.
To address the low response rate to immune checkpoint blockade (ICB) therapy, we propose a specific promoter-driven CRISPR/Cas9 system, F-PC/pHCP, that achieves permanent genomic disruption of PD-L1 and elicits a multifaceted anticancer immune response to potentiate immunotherapy. This system consists of a chlorin e6-encapsulated fluorinated dendrimer and HSP70-promoter-driven CRISPR/Cas9. F-PC/pHCP under 660 nm laser activated the HSP70 promoter and enabled the specific expression of the Cas9 protein to disrupt the PD-L1 gene, preventing immune escape. Moreover, F-PC/pHCP also induced immunogenic cell death (ICD) of tumor cells and reprogrammed the immunosuppressive tumor microenvironment. Overall, this specific promoter-driven CRISPR/Cas9 system showed great anticancer efficacy and, more importantly, stimulated an immune memory response to inhibit distant tumor growth and lung metastasis. This CRISPR/Cas9 system represents an alternative strategy for ICB therapy as well as enhanced cancer immunotherapy.
为了解决免疫检查点阻断（ICB）治疗的低反应率问题，我们提出了一种特定启动子驱动的 CRISPR/Cas9 系统，F-PC/pHCP，它实现了 PD-L1 的永久基因组破坏，并引发了多方面的抗癌免疫反应，以增强免疫治疗。该系统由氯 e6 包封的氟化树突状聚合物和 HSP70 启动子驱动的 CRISPR/Cas9 组成。在 660nm 激光激活下，F-PC/pHCP 激活 HSP70 启动子，并使 Cas9 蛋白特异性表达，从而破坏 PD-L1 基因，防止免疫逃逸。此外，F-PC/pHCP 还诱导肿瘤细胞的免疫原性细胞死亡（ICD），并重新编程免疫抑制性肿瘤微环境。总的来说，这种特定启动子驱动的 CRISPR/Cas9 系统显示出了强大的抗癌疗效，更重要的是，它刺激了免疫记忆反应，抑制了远处肿瘤的生长和肺转移。该 CRISPR/Cas9 系统为 ICB 治疗以及增强癌症免疫治疗提供了一种替代策略。
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