Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350116, Fujian, China.
Institute of Oceanography, College of Ocean, Minjiang University, Fuzhou 350108, China.
ACS Appl Mater Interfaces. 2020 Dec 23;12(51):57362-57372. doi: 10.1021/acsami.0c17660. Epub 2020 Dec 10.
The rapid development of CRISPR/Cas9 systems has opened up tantalizing prospects to sensitize cancers to chemotherapy using efficient targeted genome editing, but safety concerns and possible off-target effects of viral vectors remain a major obstacle for clinical application. Thus, the construction of novel nonviral tumor-targeting nanodelivery systems has great potential for the safe application of CRISPR/Cas9 systems for gene-chemo-combination therapy. Here, we report a polyamidoamine-aptamer-coated hollow mesoporous silica nanoparticle for the co-delivery of sorafenib and CRISPR/Cas9. The core-shell nanoparticles had good stability, enabled ultrahigh drug loading, targeted delivery, and controlled-release of the gene-drug combination. The nanocomplex showed >60% EGFR-editing efficiency without off-target effects in all nine similar sites, regulating the EGFR-PI3K-Akt pathway to inhibit angiogenesis, and exhibited a synergistic effect on cell proliferation. Importantly, the co-delivery nanosystem achieved efficient EGFR gene therapy and caused 85% tumor inhibition in a mouse model. Furthermore, the nanocomplex showed high accumulation at the tumor site and exhibited good safety with no damage to major organs. Due to these properties, the nanocomplex provides a versatile delivery approach for efficient co-loading of gene-drug combinations, allowing for precise gene editing and synergistic inhibition of tumor growth without apparent side effects on normal tissues.
CRISPR/Cas9 系统的快速发展为利用高效靶向基因组编辑使癌症对化疗敏感开辟了诱人的前景，但病毒载体的安全性问题和可能的脱靶效应仍然是临床应用的主要障碍。因此，构建新型非病毒肿瘤靶向纳米递药系统对于安全应用 CRISPR/Cas9 系统进行基因-化疗联合治疗具有巨大潜力。在这里，我们报告了一种聚酰胺-适体包覆的中空介孔硅纳米粒子，用于索拉非尼和 CRISPR/Cas9 的共递药。核壳纳米粒子具有良好的稳定性，能够实现超高药物负载、靶向递送和基因-药物组合的控制释放。该纳米复合物在所有九个相似位点均显示出 >60%的 EGFR 编辑效率，且无脱靶效应，调节 EGFR-PI3K-Akt 通路抑制血管生成，并表现出对细胞增殖的协同作用。重要的是，共递药纳米系统实现了有效的 EGFR 基因治疗，并在小鼠模型中引起了 85%的肿瘤抑制。此外，该纳米复合物在肿瘤部位有很高的积累，并表现出良好的安全性，对主要器官没有损伤。由于这些特性，该纳米复合物为高效共载基因-药物组合提供了一种多功能的递药方法，允许精确的基因编辑和协同抑制肿瘤生长，而对正常组织没有明显的副作用。
