National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China.
Sci Adv. 2024 Mar 29;10(13):eadk8264. doi: 10.1126/sciadv.adk8264.
Although CRISPR-mediated genome editing holds promise for cancer therapy, inadequate tumor targeting and potential off-target side effects hamper its outcomes. In this study, we present a strategy using cryo-shocked lung tumor cells as a CRISPR-Cas9 delivery system for cyclin-dependent kinase 4 () gene editing, which initiates synthetic lethal in KRAS-mutant non-small cell lung cancer (NSCLC). By rapidly liquid nitrogen shocking, we effectively eliminate the pathogenicity of tumor cells while preserving their structure and surface receptor activity. This delivery system enables the loaded CRISPR-Cas9 to efficiently target to lung through the capture in pulmonary capillaries and interactions with endothelial cells. In a NSCLC-bearing mouse model, the drug accumulation is increased nearly fourfold in lung, and intratumoral CDK4 expression is substantially down-regulated compared to CRISPR-Cas9 lipofectamine nanoparticles administration. Furthermore, CRISPR-Cas9 editing-mediated CDK4 ablation triggers synthetic lethal in KRAS-mutant NSCLC and prolongs the survival of mice.
虽然 CRISPR 介导的基因组编辑有望用于癌症治疗，但肿瘤靶向不足和潜在的脱靶副作用限制了其效果。在这项研究中，我们提出了一种策略，使用冷冻冲击的肺肿瘤细胞作为 CRISPR-Cas9 传递系统，对周期蛋白依赖性激酶 4 () 基因进行编辑，从而在 KRAS 突变型非小细胞肺癌 (NSCLC) 中引发合成致死。通过快速液氮冲击，我们有效地消除了肿瘤细胞的致病性，同时保持了它们的结构和表面受体活性。这种传递系统使负载的 CRISPR-Cas9 能够通过在肺毛细血管中的捕获和与内皮细胞的相互作用，有效地靶向肺部。在携带 NSCLC 的小鼠模型中，与 CRISPR-Cas9 脂质体纳米颗粒给药相比，药物在肺部的积累增加了近四倍，并且肿瘤内 CDK4 表达显著下调。此外，CRISPR-Cas9 编辑介导的 CDK4 缺失在 KRAS 突变型 NSCLC 中引发合成致死，并延长了小鼠的存活时间。
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