Author: Liu, Zhenguang ; Yu, Ruihong ; Zhao, Guofang ; Song, Zuchen ; Sun, Yuechao ; Cai, Ting ; Jiao, Lina ; Zhang, Shun ; Liu, Huina ; Hu, Yaoren ; Jin, Lan ; Li, Entao

At the end of 2019, SARS-CoV-2 emerged and rapidly spread, having a profound negative impact on human health and socioeconomic conditions. In response to this unprecedented global health crisis, significant advancements were made in the mRNA vaccine technology. In this study, we have compared the difference between two SARS-CoV-2 receptor-binding domain (RBD) mRNA-Lipid nanoparticle (LNP) vaccines prepared from two different ionizable cationic lipids: ALC-0315 and MC3. Characterization of RBD mRNA-LNPs showed that both MC3-LNP and ALC-0315-LNP are highly uniform and stable. Furthermore, we assessed the humoral immune response in mice after immunization; our findings indicated that both vaccine formulations effectively enhanced the formation and differentiation of germinal center (GC). Notably, the mice immunized with the ALC-0315-LNP vaccine elicited higher levels of IgG and its subclasses and significantly enhanced the activation of dendritic cells and T cells in draining lymph nodes (dLNs) compared to those immunized with the MC3-LNP vaccine. Further analysis of the T cell phenotype after splenic restimulation showed that mice injected with both LNP mRNA vaccines had significantly increased activation of the splenic T cells and Th1-type cytokine production. In addition, our finding showed that both LNP mRNA vaccines significantly increased the proportions of follicular helper T cells (Tfh) and long-lasting plasma cells in the dLNs of mice on day 14 postimmunization compared to control. In conclusion, both ALC-0315 and MC3 exhibited good stability and immunogenicity as mRNA-LNP recipes, but the ALC-0315-based mRNA-LNP vaccine showed higher efficacy in humoral and cellular immune responses compared to MC3.

01 Sep 2023·Small Methods

Understanding Intracellular Biology to Improve mRNA Delivery by Lipid Nanoparticles

Article

Author: Peel, Samantha ; Sonzini, Silvia ; Pereira, Sara ; Jones, Arwyn Tomos ; Iyer, Preeti ; Engkvist, Ola ; Porebski, Benjamin Thomas ; Hunter, Morag Rose ; Sabirsh, Alan ; Odunze, Uchechukwu ; Desai, Arpan Shailesh ; Ross-Thriepland, Douglas ; Lloyd, Rebecca Louise ; Cui, Lili

AbstractPoor understanding of intracellular delivery and targeting hinders development of nucleic acid‐based therapeutics transported by nanoparticles. Utilizing a siRNA‐targeting and small molecule profiling approach with advanced imaging and machine learning biological insights is generated into the mechanism of lipid nanoparticle (MC3‐LNP) delivery of mRNA. This workflow is termed Advanced Cellular and Endocytic profiling for Intracellular Delivery (ACE‐ID). A cell‐based imaging assay and perturbation of 178 targets relevant to intracellular trafficking is used to identify corresponding effects on functional mRNA delivery. Targets improving delivery are analyzed by extracting data‐rich phenotypic fingerprints from images using advanced image analysis algorithms. Machine learning is used to determine key features correlating with enhanced delivery, identifying fluid‐phase endocytosis as a productive cellular entry route. With this new knowledge, MC3‐LNP is re‐engineered to target macropinocytosis, and this significantly improves mRNA delivery in vitro and in vivo. The ACE‐ID approach can be broadly applicable for optimizing nanomedicine‐based intracellular delivery systems and has the potential to accelerate the development of delivery systems for nucleic acid‐based therapeutics.

01 May 2023·Advanced Healthcare Materials

Novel Ionizable Lipid Nanoparticles for SARS‐CoV‐2 Omicron mRNA Delivery

Article

Author: Zhang, Honglei ; Yang, Jing ; Yu, Changxiao ; Cao, Yiming ; Wang, Shengqi ; Zhang, Zhen ; Song, Gengshen ; Long, Jinrong ; Sang, Ye ; Wang, Huanyu ; Wang, Xin ; Lu, Haitao

AbstractmRNA‐based therapy has emerged as the most promising nucleic acid therapy in the fight against COVID‐19. However, a safe and efficacious systemic delivery remains a challenge for mRNA therapy. Lipid nanoparticles (LNPs) are currently widely used in mRNA delivery vehicles. Here, a series of ionizable LNPs is rationally designed. YK009‐LNP is an optimal delivery platform to carry mRNA. YK009‐LNP exhibits higher mRNA delivery efficiency, a more favorable biodistribution pattern, and better safety than the approved MC3‐LNP. In addition, mRNA encoding severe acute respiratory syndrome coronavirus 2 Omicron receptor binding domain protein is synthesized and intramuscular administration of mice with YK009‐LNP‐Omicron mRNA induces a robust immune response and immune protective effect. A novel mRNA delivery vehicle with more powerful delivery efficiency and better safety than the approved LNPs is provided here.

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Indication	Highest Phase	Country/Location	Organization	Date
Autoimmune Diseases	Preclinical	-	Alnylam Pharmaceuticals, Inc.	-
Neoplasms	Preclinical	-	Alnylam Pharmaceuticals, Inc.	-

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