信使核糖核酸
内部核糖体进入位点
核糖核酸
环状RNA
RNA干扰
生物
分子生物学
翻译(生物学)
基因
遗传学
作者
Jiali Yang,Jiafeng Zhu,Yiyun Chen,Yaran Du,Yiling Tan,Linpeng Wu,Jiejie Sun,Mengting Zhai,Lixiang Wei,Na Li,Ke Huang,Qiangbo Hou,Zhenbo Tong,Andreas Bechthold,Zhenhua Sun,Chijian Zuo
标识
DOI:10.1101/2021.11.01.466725
摘要
Abstract The application of mRNA as a novel kind of vaccine has been proved recently, due to the emergence use authorization (EUA) by FDA for the two COVID-19 mRNA vaccines developed by Moderna and BioNTech. Both of the two vaccines are based on canonical linear mRNA, and encapsulated by lipid nanoparticle (LNP). Circular mRNA, which is found to mediate potent and durable protein expression, is an emerging technology recently. Owing to its simplicity of manufacturing and superior performance of protein expression, circular mRNA is believed to be a disruptor for mRNA area. However, the application of circular mRNA is still at an initiation stage, proof of concept for its usage as future medicine or vaccine is necessary. In the current study, we established a novel kind of circular mRNA, termed C-RNA, based on Echovirus 29 (E29)-derived internal ribosome entry sites (IRES) and newly designed homology arms and RNA spacers. Our results demonstrated that this kind of circular mRNA is able to mediate strong and durable protein expression, compared to typical linear mRNA. Moreover, for the first time, our study demonstrated that direct intratumoral administration of C-RNA encoding a mixture of cytokines achieved successful modulation of intratumoral and systematic anti-tumor immune responses and finally leading to an enhancement of anti-PD-1 antibody-induced tumor repression in syngeneic mouse model. Additionally, after an optimization of the circular mRNA formulation, a significant improvement of C-RNA mediated protein expression was observed. With this optimized formulation, C-RNA induced enhanced anti-tumor effect via intratumoral administration and elicited significant activation of tumor-infiltrated total T cells and CD8 + T cells. Collectively, we established C-RNA, a novel circular mRNA platform, and demonstrated that it can be applied for direct intratumoral administration for cancer therapy.
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