Chimeric RNA-binding protein-based killing switch targeting hepatocellular carcinoma cells.
Chimeric RNA-binding protein-based killing switch targeting hepatocellular carcinoma cells.
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基于嵌合RNA结合蛋白的杀伤开关靶向肝细胞癌细胞
DOI：
10.1016/j.omtn.2021.08.012
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发表时间：
2021-09-03
期刊：
影响因子：
--
通讯作者：
Ding S
中科院分区：
文献类型：
--
作者：
Yang J;Ding S
癌细胞特异性杀伤开关是一种合成电路，作为一种智能武器开发出来，专门用于清除恶性细胞。RNA传递的合成电路为控制溶瘤功能提供了更安全的手段，其中开发了蛋白质分解反应衣壳-Cnot7以实现逻辑计算和模块化设计。不幸的是，尽管含有这些衣壳-cNOT7的电路在作为复制子引入时表现出了良好的性能，但在修饰的mRNA(ModRNA)递送中，性能并不是很好。为了改善这种情况，需要开发适用于modRNA递送的替代模块。一个有吸引力的选择是RNA结合蛋白(RBP)/核糖开关。在这项研究中，限制性商业惯例是通过融合降解和裂解位点来设计的。测试了这些嵌合限制性商业惯例与基于蛋白降解的传感单元的相容性。实现了8个两输入逻辑门和4个三输入逻辑门。在构建了这个基于RBP的嵌合系统后，我们构建了一个肝癌细胞特异性杀伤电路，该电路使用了两个基于蛋白分解的传感单元、一个两输入逻辑或门和一个防泄漏的凋亡诱导执行器，该电路区分了肝癌细胞并在IMR90-PLC/PRF/5混合群体中诱导了细胞凋亡。在本研究中，我们构建了一种新型的嵌合RBP系统。利用嵌合式RBP实现了8个2输入逻辑门和4个3输入逻辑门。还开发了一种肝癌细胞特异性杀伤电路。这一新的系统具有兼容性和可扩展性，在肿瘤溶解治疗中具有广泛的应用潜力。
Cancer cell-specific killing switches are synthetic circuits developed as an intelligent weapon to specifically eliminate malignant cells. RNA-delivered synthetic circuits provide safer means to control oncolytic functions, in which proteolysis-responding capsid-cNOT7 is developed to enable logic computation and modular design. Unfortunately, although circuits containing these capsid-cNOT7s exhibited good performance when introduced as replicons, in modified mRNA (modRNA) delivery, the performance was not quite as good. To improve this situation, alternative modules suitable for modRNA delivery need to be developed. An attractive option is RNA-binding protein (RBP)/riboswitches. In this study, RBPs were engineered by fusing with degron and cleavage sites. The compatibility of these chimeric RBPs with proteolysis-based sensing units were tested. Eight two-input logic gates and four three-input logic gates were implemented. After building this chimeric RBP-based system, we constructed a hepatocellular carcinoma (HCC) cell-specific killing circuit using two proteolysis-based sensing units, a two-input logic OR gate, and a leakproof apoptosis-inducing actuator, which distinguished HCC cells and induced apoptosis in a mixed IMR90-PLC/PRF/5 population. In this study, we built a novel chimeric RBP-based system. Eight two-input logic gates and four three-input logic gates were implemented using the chimeric RBPs. An HCC cell-specific killing circuit was also developed. This novel system is compatible and scalable, indicating versatile applicable potential in oncolytic therapy.
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