Golba Bianka, De Franceschi Irene, Zhong Zifu, Schuijs Martijn J, Brenis Gomez Claudia M, Lauwers Heleen, Louage Benoit, Sheshi Iasona, Badi Nezha, De Geest Bruno G, Du Prez Filip E
Department of Pharmaceutics, Ghent University, Ghent 9000, Belgium.
Polymer Chemistry Research Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Faculty of Sciences, Ghent University, Ghent 9000, Belgium.
J Am Chem Soc. 2025 Jul 30;147(30):26934-26943. doi: 10.1021/jacs.5c09030. Epub 2025 Jul 21.
Lipid nanoparticles (LNPs), containing ionizable cationic lipids, have attracted widespread interest in recent years, particularly following their use as mRNA delivery systems for COVID-19 vaccines. Here, we report on the combinatorial synthesis of galloyl amidoamine-based ionizable lipids. Starting from methyl gallate, three alkyl tails were substituted onto the aromatic ring, and the carboxylic acid was transformed into an ionizable tertiary amine headgroup. Optimization of the synthetic protocol resulted in a scalable, chromatography-free procedure requiring as few as two transformation steps and yielding a library of 43 different lipids in high yield (>88%). By varying the ionizable amine headgroup and the length, saturation, and branching of the alkyl tails, we found that the length of the lipid tail significantly impacted solubility and mRNA encapsulation efficiency. Trialkyl lipids comprising unsaturated heptyl and octyl tails enabled the formulation of sub-150 nm LNPs with encapsulation efficiencies exceeding 85%. Benchmarking experiments against a commercial MC3 LNP formulation identified four lipids that enabled potent mRNA transfection in vitro. Moreover, in vivo studies in mice with selected LNP formulations indicated that three lipids performed on par with MC3 in terms of luciferase reporter-protein expression in the liver and spleen after intravenous administration. Additionally, these lipids did not show any toxicity in the spleen and liver. These results clearly highlight the translational potential of trialkyl galloyl amidoamine lipids and more particularly for mRNA-based therapies.
含有可电离阳离子脂质的脂质纳米颗粒（LNPs）近年来引起了广泛关注，尤其是在其作为新冠疫苗的mRNA递送系统使用之后。在此，我们报告基于没食子酰氨基胺的可电离脂质的组合合成。从没食子酸甲酯开始，在芳香环上取代三条烷基链，并将羧酸转化为可电离的叔胺头部基团。合成方案的优化产生了一种可扩展的、无需色谱法的程序，该程序只需少至两个转化步骤，就能以高产率（>88%）得到包含43种不同脂质的文库。通过改变可电离胺头部基团以及烷基链的长度、饱和度和支化情况，我们发现脂质尾部的长度对溶解度和mRNA包封效率有显著影响。包含不饱和庚基和辛基尾部的三烷基脂质能够制备出直径小于150 nm的LNPs，其包封效率超过85%。与市售MC3 LNP制剂进行的基准实验鉴定出四种能够在体外实现高效mRNA转染的脂质。此外，对选定LNP制剂在小鼠体内的研究表明，在静脉给药后，三种脂质在肝脏和脾脏中的荧光素酶报告蛋白表达方面与MC3表现相当。此外，这些脂质在脾脏和肝脏中未显示出任何毒性。这些结果清楚地突出了三烷基没食子酰氨基胺脂质的转化潜力，尤其是在基于mRNA的治疗方面。
