Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seongbuk-Gu, Seoul 136-791, South Korea.
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seongbuk-Gu, Seoul 136-791, South Korea; Division fo Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, South Korea.
J Control Release. 2017 Nov 28;266:8-16. doi: 10.1016/j.jconrel.2017.09.013. Epub 2017 Sep 12.
An intracellular delivery system for CRISPR/Cas9 is crucial for its application as a therapeutic genome editing technology in a broad range of diseases. Current vehicles carrying CRISPR/Cas9 limit in vivo delivery because of low tolerance and immunogenicity; thus, the in vivo delivery of genome editing remains challenging. Here, we report that cancer-derived exosomes function as natural carriers that can efficiently deliver CRISPR/Cas9 plasmids to cancer. Compared to epithelial cell-derived exosomes, cancer-derived exosomes provide potential vehicles for effective in vivo delivery via selective accumulation in ovarian cancer tumors of SKOV3 xenograft mice, most likely because of their cell tropism. CRISPR/Cas9-loaded exosomes can suppress expression of poly (ADP-ribose) polymerase-1 (PARP-1), resulting in the induction of apoptosis in ovarian cancer. Furthermore, the inhibition of PARP-1 by CRISPR/Cas9-mediated genome editing enhances the chemosensitivity to cisplatin, showing synergistic cytotoxicity. Based on these results, tumor-derived exosomes may be very promising for cancer therapeutics in the future.
CRISPR/Cas9 的细胞内递呈系统对于将其作为一种治疗性基因组编辑技术广泛应用于多种疾病至关重要。目前携带 CRISPR/Cas9 的载体由于低耐受性和免疫原性而限制了其在体内的递呈；因此，基因组编辑的体内递呈仍然具有挑战性。在这里，我们报告说，癌症衍生的外体作为天然载体，可以有效地将 CRISPR/Cas9 质粒递送至癌症。与上皮细胞衍生的外体相比，癌症衍生的外体通过选择性积累在 SKOV3 异种移植小鼠的卵巢癌肿瘤中提供了有效的体内递呈的潜在载体，这很可能是因为它们的细胞嗜性。负载 CRISPR/Cas9 的外体可以抑制聚（ADP-核糖）聚合酶-1（PARP-1）的表达，导致卵巢癌细胞凋亡的诱导。此外，CRISPR/Cas9 介导的基因组编辑抑制 PARP-1 增强了顺铂的化疗敏感性，表现出协同细胞毒性。基于这些结果，肿瘤衍生的外体在未来可能是非常有前途的癌症治疗方法。
Zotero 插件