Honglei Zhang, Jingxuan Ma, Lijie Jin, Yuqing Ma, Kai Dong, Jing Li, Fei Yu, Gengshen Song
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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.
期刊介绍：
The journal provides a unique forum for scientific publication of high-quality research that is exclusively focused on translational aspects of drug delivery. Rationally developed, effective delivery systems can potentially affect clinical outcome in different disease conditions.
Research focused on the following areas of translational drug delivery research will be considered for publication in the journal.
Designing and developing novel drug delivery systems, with a focus on their application to disease conditions;
Preclinical and clinical data related to drug delivery systems;
Drug distribution, pharmacokinetics, clearance, with drug delivery systems as compared to traditional dosing to demonstrate beneficial outcomes
Short-term and long-term biocompatibility of drug delivery systems, host response;
Biomaterials with growth factors for stem-cell differentiation in regenerative medicine and tissue engineering;
Image-guided drug therapy,
Nanomedicine;
Devices for drug delivery and drug/device combination products.
In addition to original full-length papers, communications, and reviews, the journal includes editorials, reports of future meetings, research highlights, and announcements pertaining to the activities of the Controlled Release Society.
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