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.

中文翻译：

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通过用于白细胞介素 30 基因组编辑的 CRISPR 递送纳米平台预防前列腺癌转移


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） 是一种 PC 进展驱动因素，其抑制对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） 加载 CRISPR-Cas9gRNA 以删除人 IL30 （hIL30） 基因，并用抗 PSCA-Abs （Cas9hIL30-PSCA NPs） 功能化。在肺转移的异种移植模型中，在体内检查 了 NPs 靶向 IL-30 的效率和 PC 细胞的转移潜力，并在 体外使用两个含有器官芯片 （2-OC） 的 IL30 + PC 内皮细胞的 3D 球体与模拟肺的球体或骨髓 （BM） 生态位模拟支架共培养。Cas9hIL30-PSCA NPs 表现出循环稳定性、基因组编辑效率，无脱靶效应和器官毒性。在携带循环 PC 细胞和肿瘤微栓子的小鼠中静脉注射 3 剂/13 天或 5 剂/20 天的 NPs 严重阻碍了肺转移。Cas9hIL30-PSCA NPs 抑制 PC 细胞增殖和 IL-30 和转移驱动因素的表达，例如 CXCR2 、 CXCR4 、 IGF1 、 L1CAM 、 METAP2 、 MMP2 和 TNFSF10，而 CDH1 上调。PC-Lung 和 PC-BM 2-OCs 显示 Cas9hIL30-PSCA NPs 抑制 PC 细胞释放 CXCL2/GROβ，这与转移内髓系细胞浸润有关，以及 DKK1、OPG 和 IL-6 的释放，促进内皮网络形成和癌细胞迁移。开发用于选择性 CRISPR 介导的 IL-30 基因缺失的患者定制纳米平台是对抗 PC 进展的临床有价值的工具。