Cristiano Fieni, Stefania Livia Ciummo, Carlo Sorrentino, Simona Marchetti, Simone Vespa, Paola Lanuti, Lavinia Vittoria Lotti, Emma Di Carlo
{"title":"通过CRISPR递送纳米平台进行白细胞介素-30基因组编辑,预防前列腺癌转移。","authors":"Cristiano Fieni, Stefania Livia Ciummo, Carlo Sorrentino, Simona Marchetti, Simone Vespa, Paola Lanuti, Lavinia Vittoria Lotti, Emma Di Carlo","doi":"10.1016/j.ymthe.2024.09.011","DOIUrl":null,"url":null,"abstract":"<p><p>Prostate-cancer (PC) is a leading cause of cancer-related deaths in men worldwide. Interleukin-(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 human(h)IL30-gene and functionalized with anti-PSCA-Abs (Cas9hIL30-PSCA-NPs). Efficiency of the NPs in targeting IL30 and metastatic potential of PC cells was examined in vivo, in xenograft models of lung metastasis, and in vitro, by using 2-Organ-on-Chip (2-OC), containing 3D-spheroids of IL30<sup>+</sup>PC-Endothelial-Cell(EC) 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 micro-emboli substantially hindered lung metastasization. Cas9hIL30-PSCA-NPs inhibited PC cell proliferation and expression of IL30 and metastasis-drivers, such as CXCR2, CXCR4, IGF1, L1CAM, METAP2, MMP2 and TNFSF10, whereas CDH1 was up-regulated. PC-Lung and PC-BM 2-OCs revealed that Cas9hIL30-PSCA-NPs suppressed PC cell release of CXCL2/GROβ, which in vivo was associated with intra-metastatic myeloid cell infiltrates, and of DKK1, OPG and IL6, which in vitro boosted endothelial-network formation and cancer cell migration. Development of a patient-tailored nanoplatform for selective CRISPR-mediated IL30 gene deletion is a clinically valuable tool against PC progression.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":null,"pages":null},"PeriodicalIF":12.1000,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Prevention of Prostate Cancer Metastasis by a CRISPR-delivering Nanoplatform for Interleukin-30 Genome Editing.\",\"authors\":\"Cristiano Fieni, Stefania Livia Ciummo, Carlo Sorrentino, Simona Marchetti, Simone Vespa, Paola Lanuti, Lavinia Vittoria Lotti, Emma Di Carlo\",\"doi\":\"10.1016/j.ymthe.2024.09.011\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Prostate-cancer (PC) is a leading cause of cancer-related deaths in men worldwide. Interleukin-(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 human(h)IL30-gene and functionalized with anti-PSCA-Abs (Cas9hIL30-PSCA-NPs). Efficiency of the NPs in targeting IL30 and metastatic potential of PC cells was examined in vivo, in xenograft models of lung metastasis, and in vitro, by using 2-Organ-on-Chip (2-OC), containing 3D-spheroids of IL30<sup>+</sup>PC-Endothelial-Cell(EC) 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 micro-emboli substantially hindered lung metastasization. Cas9hIL30-PSCA-NPs inhibited PC cell proliferation and expression of IL30 and metastasis-drivers, such as CXCR2, CXCR4, IGF1, L1CAM, METAP2, MMP2 and TNFSF10, whereas CDH1 was up-regulated. PC-Lung and PC-BM 2-OCs revealed that Cas9hIL30-PSCA-NPs suppressed PC cell release of CXCL2/GROβ, which in vivo was associated with intra-metastatic myeloid cell infiltrates, and of DKK1, OPG and IL6, which in vitro boosted endothelial-network formation and cancer cell migration. Development of a patient-tailored nanoplatform for selective CRISPR-mediated IL30 gene deletion is a clinically valuable tool against PC progression.</p>\",\"PeriodicalId\":19020,\"journal\":{\"name\":\"Molecular Therapy\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":12.1000,\"publicationDate\":\"2024-09-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ymthe.2024.09.011\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2024.09.011","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
Prevention of Prostate Cancer Metastasis by a CRISPR-delivering Nanoplatform for Interleukin-30 Genome Editing.
Prostate-cancer (PC) is a leading cause of cancer-related deaths in men worldwide. Interleukin-(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 human(h)IL30-gene and functionalized with anti-PSCA-Abs (Cas9hIL30-PSCA-NPs). Efficiency of the NPs in targeting IL30 and metastatic potential of PC cells was examined in vivo, in xenograft models of lung metastasis, and in vitro, by using 2-Organ-on-Chip (2-OC), containing 3D-spheroids of IL30+PC-Endothelial-Cell(EC) 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 micro-emboli substantially hindered lung metastasization. Cas9hIL30-PSCA-NPs inhibited PC cell proliferation and expression of IL30 and metastasis-drivers, such as CXCR2, CXCR4, IGF1, L1CAM, METAP2, MMP2 and TNFSF10, whereas CDH1 was up-regulated. PC-Lung and PC-BM 2-OCs revealed that Cas9hIL30-PSCA-NPs suppressed PC cell release of CXCL2/GROβ, which in vivo was associated with intra-metastatic myeloid cell infiltrates, and of DKK1, OPG and IL6, which in vitro boosted endothelial-network formation and cancer cell migration. Development of a patient-tailored nanoplatform for selective CRISPR-mediated IL30 gene deletion is a clinically valuable tool against PC progression.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.