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Characterization of mRNA-LNP structural features and mechanisms for enhanced mRNA vaccine immunogenicity
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2024-11-13 , DOI: 10.1016/j.jconrel.2024.11.007 Kangzeng Wu, Fengwei Xu, Yongchao Dai, Shanshan Jin, Anjie Zheng, Ning Zhang, Yuhong Xu
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2024-11-13 , DOI: 10.1016/j.jconrel.2024.11.007 Kangzeng Wu, Fengwei Xu, Yongchao Dai, Shanshan Jin, Anjie Zheng, Ning Zhang, Yuhong Xu
Lipid nanoparticles (LNPs) used for nonviral gene delivery have achieved significant success, particularly in COVID-19 mRNA vaccines. LNPs are routinely characterized by their particle size, polydispersity, and mRNA loading efficiency. However, the internal structure of these particles has not been specified, despite evidence showing that LNPs can be highly heterogeneous, with variations in lipid composition and preparation methods. How these structural features contributed to mRNA LNP vaccine activities is also unclear. In this study, we prepared LNPs with distinctly different internal structures. They were named the emulsion-like LNPs (eLNPs) and membrane-rich LNPs (mLNPs) respectively and compared with the classic “bleb” structure LNPs (cLNPs). The eLNPs contained higher molar percent of the ionizable lipid and lower molar percent of DSPC and cholesterol. The different lipid organization structures lead to varying mRNA delivery activities in vitro and in vivo. After intramuscular injection, eLNPs remained at the injection site and expressed antigens locally. The resulted immune responses had a very fast onset (higher titer at week 2) and lasted longer and stronger (higher titers at week 8) than other LNPs (cLNPs and mLNPs). We hypothesize that the rapid onset and local expression of antigens by muscle cells in the eLNP groups may be favored by the antigen recognition and presentation process, despite the overall mRNA expression activities was not as high especially in liver and other organ. Our data support that eLNPs are potentially the more suitable delivery system for mRNA vaccine due to their high immunogenicity and low systemic toxicity.
中文翻译:
mRNA-LNP 结构特征的表征和增强 mRNA 疫苗免疫原性的机制
用于非病毒基因递送的脂质纳米颗粒 (LNP) 取得了重大成功,尤其是在 COVID-19 mRNA 疫苗中。LNP 通常通过其粒径、多分散性和 mRNA 负载效率来表征。然而,尽管有证据表明 LNP 可能具有高度异质性,脂质组成和制备方法各不相同,但这些颗粒的内部结构尚未确定。这些结构特征如何促进 mRNA LNP 疫苗活性也尚不清楚。在这项研究中,我们制备了具有明显不同内部结构的 LNP。它们分别被命名为乳液状 LNP (eLNPs) 和富膜 LNPs (mLNPs),并与经典的 “bleb” 结构 LNPs (cLNPs) 进行比较。eLNPs 含有较高的可电离脂质摩尔百分比和较低的 DSPC 和胆固醇的摩尔百分比。不同的脂质组织结构导致体外和体内不同的 mRNA 递送活性。肌内注射后,eLNPs 留在注射部位并局部表达抗原。与其他 LNP (cLNPs 和 mLNPs) 相比,产生的免疫反应起效非常快 (第 2 周滴度更高),持续时间更长、更强 (第 8 周滴度更高)。我们假设 eLNP 组中肌肉细胞抗原的快速起义和局部表达可能有利于抗原识别和呈递过程,尽管总体 mRNA 表达活性没有那么高,尤其是在肝脏和其他器官中。我们的数据支持 eLNPs 可能更适合 mRNA 疫苗的递送系统,因为它们具有高免疫原性和低全身毒性。
更新日期:2024-11-13
中文翻译:
mRNA-LNP 结构特征的表征和增强 mRNA 疫苗免疫原性的机制
用于非病毒基因递送的脂质纳米颗粒 (LNP) 取得了重大成功,尤其是在 COVID-19 mRNA 疫苗中。LNP 通常通过其粒径、多分散性和 mRNA 负载效率来表征。然而,尽管有证据表明 LNP 可能具有高度异质性,脂质组成和制备方法各不相同,但这些颗粒的内部结构尚未确定。这些结构特征如何促进 mRNA LNP 疫苗活性也尚不清楚。在这项研究中,我们制备了具有明显不同内部结构的 LNP。它们分别被命名为乳液状 LNP (eLNPs) 和富膜 LNPs (mLNPs),并与经典的 “bleb” 结构 LNPs (cLNPs) 进行比较。eLNPs 含有较高的可电离脂质摩尔百分比和较低的 DSPC 和胆固醇的摩尔百分比。不同的脂质组织结构导致体外和体内不同的 mRNA 递送活性。肌内注射后,eLNPs 留在注射部位并局部表达抗原。与其他 LNP (cLNPs 和 mLNPs) 相比,产生的免疫反应起效非常快 (第 2 周滴度更高),持续时间更长、更强 (第 8 周滴度更高)。我们假设 eLNP 组中肌肉细胞抗原的快速起义和局部表达可能有利于抗原识别和呈递过程,尽管总体 mRNA 表达活性没有那么高,尤其是在肝脏和其他器官中。我们的数据支持 eLNPs 可能更适合 mRNA 疫苗的递送系统,因为它们具有高免疫原性和低全身毒性。