: 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.

Prevention of prostate cancer metastasis by a CRISPR-delivering nanoplatform for interleukin-30 genome editing / Fieni, Cristiano; Ciummo, Stefania Livia; Sorrentino, Carlo; Marchetti, Simona; Vespa, Simone; Lanuti, Paola; Lotti, Lavinia Vittoria; Di Carlo, Emma. - In: MOLECULAR THERAPY. - ISSN 1525-0016. - (2024), pp. 1-23. [10.1016/j.ymthe.2024.09.011]

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

Lotti, Lavinia Vittoria;
2024

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.
2024
CRISPR-Cas9; immunoliposomes; interleukins; metastasis; nanotechnology; prostate cancer
01 Pubblicazione su rivista::01a Articolo in rivista
Prevention of prostate cancer metastasis by a CRISPR-delivering nanoplatform for interleukin-30 genome editing / Fieni, Cristiano; Ciummo, Stefania Livia; Sorrentino, Carlo; Marchetti, Simona; Vespa, Simone; Lanuti, Paola; Lotti, Lavinia Vittoria; Di Carlo, Emma. - In: MOLECULAR THERAPY. - ISSN 1525-0016. - (2024), pp. 1-23. [10.1016/j.ymthe.2024.09.011]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1721112
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