Huang Chenxing, Jia Jianguo, Jin Kejia, Zou Yan, Tan Shudan, Lu Jing, Zhu Yizhun, Lin Jinzhong, Dai Yuxiang, Gong Hui
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China.
J Cardiovasc Transl Res. 2023 Oct;16(5):1078-1084. doi: 10.1007/s12265-023-10392-8. Epub 2023 May 8.
Lipid nanoparticle (LNP)-coated-modified RNA(modRNA) has been developed for enhancing the stability of modRNA, but it tends to accumulate in liver. The current study aimed to optimize strategy for increasing cardiac expression efficiency of modRNA. We synthesized Luciferase (Luc)-modRNA, and also developed 122Luc modRNA, a liver silencing Luc modRNA. Intramyocardial injection of naked Luc modRNA induced high bioluminescence signal in heart, but very low in other organs including liver. Luc modRNA-LNP injection showed the signal was increased by 5 folds in the heart and by 15,000 folds in the liver, compared to naked Luc modRNA group. In comparison with Luc modRNA-LNP group, the liver signal was decreased to 0.17%, while cardiac signal showed a slight drop by intramyocardial injection of 122Luc-modRNA-LNP. Our data revealed that intramyocardial injection of naked modRNA could effectively induced cardiac-specific expression. For cardiac delivery of Luc modRNA-LNP, 122modRNA-LNP enhances specificity of cardiac expression by abolishing liver signal.
脂质纳米颗粒（LNP）包被修饰的RNA（modRNA）已被开发用于提高modRNA的稳定性，但它往往会在肝脏中积累。当前研究旨在优化提高modRNA心脏表达效率的策略。我们合成了荧光素酶（Luc）-modRNA，还开发了122Luc modRNA，一种肝脏沉默Luc modRNA。心肌内注射裸Luc modRNA在心脏中诱导出高生物发光信号，但在包括肝脏在内的其他器官中非常低。与裸Luc modRNA组相比，Luc modRNA-LNP注射显示心脏中的信号增加了5倍，肝脏中的信号增加了15000倍。与Luc modRNA-LNP组相比，通过心肌内注射122Luc-modRNA-LNP，肝脏信号降至0.17%，而心脏信号略有下降。我们的数据表明，心肌内注射裸modRNA可有效诱导心脏特异性表达。对于Luc modRNA-LNP的心脏递送，122modRNA-LNP通过消除肝脏信号增强了心脏表达的特异性。
