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<p>Messenger RNA (mRNA) therapeutics have shown considerable promise across a wide range of medical applications with lipid nanoparticles (LNPs) emerging as the most clinically advanced mRNA delivery vehicles. However, the risk of off-target tissue delivery remains a concern, underscoring the need for diverse ionizable lipids to optimize LNP-based delivery systems. In this study, we designed and synthesized a library of 21 novel ionizable lipids and evaluated their potential for mRNA delivery. The resulting LNPs displayed favorable physicochemical properties and low cytotoxicity. In vitro transfection assay identified 3 high efficiency LNPs: YK-305, YK-310 and YK-319. In a mouse model, intramuscular injection of firefly luciferase (Fluc) mRNA-LNPs resulted in high transfection efficiency in muscle tissue, with significantly reduced gene expression in the liver. After encapsulating varicella zoster virus (VZV) glycoprotein E (gE)-encoding mRNA, the three LNP formulations induced robust humoral and cellular immune responses specific to the gE antigen, demonstrated improved selectivity and immunogenicity compared to SM-102, the ionizable lipid used in Moderna’s Spikevax. The safety of the gE-mRNA LNP formulations were subsequently demonstrated in a mouse model. Collectively, these findings provide a foundation for the optimization of tissue-targeting ionizable lipids and highlight their potential to advance mRNA-based vaccines in clinical applications.</p> Graphical abstract <p></p>

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Muscle-targeting LNP vaccines enable potent immune responses against varicella zoster virus

  • 期刊论文

  • 发表日期：

    2025年9月1日

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  • Honglei Zhang,
  • Jingxuan Ma,
  • Lijie Jin,
  • Yuqing Ma,
  • Kai Dong,
  • Jing Li,
  • Fei Yu,
  • Gengshen Song

摘要

Messenger RNA (mRNA) therapeutics have shown considerable promise across a wide range of medical applications with lipid nanoparticles (LNPs) emerging as the most clinically advanced mRNA delivery vehicles. However, the risk of off-target tissue delivery remains a concern, underscoring the need for diverse ionizable lipids to optimize LNP-based delivery systems. In this study, we designed and synthesized a library of 21 novel ionizable lipids and evaluated their potential for mRNA delivery. The resulting LNPs displayed favorable physicochemical properties and low cytotoxicity. In vitro transfection assay identified 3 high efficiency LNPs: YK-305, YK-310 and YK-319. In a mouse model, intramuscular injection of firefly luciferase (Fluc) mRNA-LNPs resulted in high transfection efficiency in muscle tissue, with significantly reduced gene expression in the liver. After encapsulating varicella zoster virus (VZV) glycoprotein E (gE)-encoding mRNA, the three LNP formulations induced robust humoral and cellular immune responses specific to the gE antigen, demonstrated improved selectivity and immunogenicity compared to SM-102, the ionizable lipid used in Moderna’s Spikevax. The safety of the gE-mRNA LNP formulations were subsequently demonstrated in a mouse model. Collectively, these findings provide a foundation for the optimization of tissue-targeting ionizable lipids and highlight their potential to advance mRNA-based vaccines in clinical applications.

Graphical abstract