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CRISPR 递送纳米平台抑制白细胞介素 30 基因编辑预防前列腺癌转移

Prevention of prostate cancer metastasis by a CRISPR-delivering nanoplatform for interleukin-30 genome editing.

机构信息

Department of Medicine and Sciences of Aging, "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy; Anatomic Pathology and Immuno-Oncology Unit, Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy.

Department of Medicine and Sciences of Aging, "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy.

出版信息

Mol Ther. 2024 Nov 6;32(11):3932-3954. doi: 10.1016/j.ymthe.2024.09.011. Epub 2024 Sep 7.

DOI:10.1016/j.ymthe.2024.09.011
PMID:39244641
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11573607/
Abstract

Prostate cancer (PC) is a leading cause of cancer-related deaths in men worldwide. Interleukin-30 (IL-30) is a PC progression driver, and its suppression would be strategic for fighting metastatic disease. Biocompatible lipid nanoparticles (NPs) were loaded with CRISPR-Cas9gRNA to delete the human IL30 (hIL30) gene and functionalized with anti-PSCA-Abs (Cas9hIL30-PSCA NPs). Efficiency of the NPs in targeting IL-30 and the metastatic potential of PC cells was examined in vivo in xenograft models of lung metastasis, and in vitro by using two organ-on-chip (2-OC)-containing 3D spheroids of IL30 PC-endothelial cell co-cultures in circuit with either lung-mimicking spheroids or bone marrow (BM)-niche-mimicking scaffolds. Cas9hIL30-PSCA NPs demonstrated circulation stability, genome editing efficiency, without off-target effects and organ toxicity. Intravenous injection of three doses/13 days, or five doses/20 days, of NPs in mice bearing circulating PC cells and tumor microemboli substantially hindered lung metastasization. Cas9hIL30-PSCA NPs inhibited PC cell proliferation and expression of IL-30 and metastasis drivers, such as CXCR2, CXCR4, IGF1, L1CAM, METAP2, MMP2, and TNFSF10, whereas CDH1 was upregulated. PC-Lung and PC-BM 2-OCs revealed that Cas9hIL30-PSCA NPs suppressed PC cell release of CXCL2/GROβ, which was associated with intra-metastatic myeloid cell infiltrates, and of DKK1, OPG, and IL-6, which boosted endothelial network formation and cancer cell migration. Development of a patient-tailored nanoplatform for selective CRISPR-mediated IL-30 gene deletion is a clinically valuable tool against PC progression.

摘要

前列腺癌（PC）是全球男性癌症相关死亡的主要原因。白细胞介素-30（IL-30）是 PC 进展的驱动因素，抑制其表达对于对抗转移性疾病具有战略意义。生物相容性脂质纳米颗粒（NPs）被加载 CRISPR-Cas9gRNA 以删除人 IL30（hIL30）基因，并与抗 PSCA-Abs 功能化（Cas9hIL30-PSCA NPs）。在肺转移的异种移植模型中，体内检查了 NPs 靶向 IL-30 的效率和 PC 细胞的转移潜力，在含有 3D 球体的两个器官芯片（2-OC）中，通过使用 IL30 PC-内皮细胞共培养物的两种器官芯片（2-OC）进行了体外研究，与肺模拟球体或骨髓（BM）-巢模拟支架进行了回路。 Cas9hIL30-PSCA NPs 表现出循环稳定性、基因组编辑效率，没有脱靶效应和器官毒性。在携带循环 PC 细胞和肿瘤微栓塞的小鼠中，静脉注射三剂/13 天或五剂/20 天的 NPs，可显著抑制肺转移。 Cas9hIL30-PSCA NPs 抑制了 PC 细胞的增殖和 IL-30 以及转移驱动因子的表达，如 CXCR2、CXCR4、IGF1、L1CAM、METAP2、MMP2 和 TNFSF10，而 CDH1 上调。 PC-Lung 和 PC-BM 2-OC 显示，Cas9hIL30-PSCA NPs 抑制了 PC 细胞释放 CXCL2/GROβ，这与转移间髓样细胞浸润有关，以及 DKK1、OPG 和 IL-6，这促进了内皮网络形成和癌细胞迁移。开发一种针对患者的、选择性的基于 CRISPR 的 IL-30 基因缺失的纳米平台是一种针对 PC 进展的具有临床价值的工具。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a706/11573607/0974c333bfb3/gr6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a706/11573607/2395502196d0/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a706/11573607/19f7efdc6324/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a706/11573607/18081d63df46/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a706/11573607/4748aad3ccaf/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a706/11573607/673e6bdac014/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a706/11573607/0974c333bfb3/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a706/11573607/5a69cc240bc0/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a706/11573607/2395502196d0/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a706/11573607/19f7efdc6324/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a706/11573607/18081d63df46/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a706/11573607/4748aad3ccaf/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a706/11573607/673e6bdac014/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a706/11573607/0974c333bfb3/gr6.jpg

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J Exp Clin Cancer Res. 2023 Dec 12;42(1):336. doi: 10.1186/s13046-023-02902-y.
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Modulation of cell cycle increases CRISPR-mediated homology-directed DNA repair.细胞周期的调控增强了CRISPR介导的同源定向DNA修复。
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An Update on the Application of CRISPR Technology in Clinical Practice.CRISPR 技术在临床实践中的应用进展更新。
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