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mRNA疗法具有广泛应用于各种疾病防治的潜力，将mRNA安全、有效递送至靶细胞是mRNA疗法的核心技术。近年来，研究人员开发了一种基于病毒样颗粒（Virus-like particle, VLP）的mRNA递送技术。VLP是利用病毒结构蛋白识别常规mRNA而组装形成的一种与天然病毒结构类似的颗粒，兼具病毒载体靶向递送效率高和常规mRNA安全性好的优势。甲病毒属（Alphaviruses）是最常用的病毒载体之一，本研究利用甲病毒成员委内瑞拉马脑炎病毒（Venezuelan equine encephalitis virus, VEEV）载体，首次建立了一种基于甲病毒VLP的常规mRNA递送方法。结果表明在常规mRNA中引入VEEV基因组包装信号（Packaging signal, PS）序列，可使mRNA被VEEV结构蛋白识别，并组装形成VLP释放至细胞外，VLP感染可将mRNA递送至细胞内表达目的蛋白。通过检测PS在mRNA中的位置和数量、VEEV非结构蛋白反式表达等对VLP包装和目的蛋白表达的影响，为后续VLP优化提供重要基础。本研究建立的基于甲病毒VLP的mRNA递送平台为今后mRNA递送研究提供一种新策略。
Abstract：mRNA therapeutics hold great potential for the prevention and treatment of a wide range of diseases. A key challenge in this field lies in the safe and effective delivery of mRNA to target cells. In recent years, a novel mRNA delivery strategy has been developed based on virus-like particles(VLPs). VLPs are nanoscale structures that resemble native viruses and are formed by the self-assembly of viral structural proteins around exogenous mRNA. This approach combines the high targeting efficiency of viral vectors with the favorable safety profile of non-viral mRNA delivery systems. Alphaviruses are among the most widely used viral vectors. In this study, we utilized Venezuelan equine encephalitis virus(VEEV) a representative alphavirus, to establish for the first time a VLP-based delivery method for conventional(non-replicating) mRNA. Our results demonstrated that the incorporation of the VEEV genome packaging signal(PS) into conventional mRNA allowed for its recognition by VEEV structural proteins, resulting in the assembly and extracellular release of the VLPs. These VLPs were capable of effectively delivering mRNA into recipient cells to drive the expression of the encoded protein. Furthermore, we investigated how the position and copy number of the PS sequence within mRNA, as well as the trans-expression of VEEV non-structural proteins, influenced VLP packaging and downstream protein expression. These findings provide important mechanistic insights for the optimization of alphavirus VLP-based mRNA delivery systems. In conclusion, the alphavirus VLP-based platform established in this study offers a promising new strategy for the development of mRNA delivery technologies.
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基本信息:
DOI：10.13242/j.cnki.bingduxuebao.250096
中图分类号:Q78;R456
引用信息:
[1]王鑫,罗鑫,潘晓玲,等.基于甲病毒病毒样颗粒的mRNA递送技术研究[J].病毒学报,2025,41(05):1403-1414.DOI:10.13242/j.cnki.bingduxuebao.250096.
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