Combinatorial synthesis and evaluation of trialkyl galloyl amidoamine ionizable lipids for mRNA formulation
- Author
- Bianka Golba, Irene De Franceschi (UGent) , Zifu Zhong (UGent) , Martijn Schuijs (UGent) , Claudia Mariela Brenis Gómez (UGent) , Heleen Lauwers (UGent) , Benoit Louage (UGent) , Iasona Sheshi (UGent) , Nezha Badi (UGent) , Bruno De Geest (UGent) and Filip Du Prez (UGent)
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- Cut-and-paste chemistry: from circular plastics to immunotherapeutics
- Magnetische resonantieapparatuur voor gevorderd materiaalonderzoek: moleculaire karakterisering van vaste, zachte, homogene en heterogene materie in de ontwikkeling van geavanceerde functionele materialen en chemische katalyse
- Routine NMR Analysis Equipment for Small Molecule Characterisation.
- Abstract
- 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.
- Keywords
- GALLIC ACID, SYSTEMS
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01K6ABT82F8XJPR4PQ3N9FS0R4
- MLA
- Golba, Bianka, et al. “Combinatorial Synthesis and Evaluation of Trialkyl Galloyl Amidoamine Ionizable Lipids for MRNA Formulation.” JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 147, no. 30, 2025, pp. 26934–43, doi:10.1021/jacs.5c09030.
- APA
- Golba, B., De Franceschi, I., Zhong, Z., Schuijs, M., Brenis Gómez, C. M., Lauwers, H., … Du Prez, F. (2025). Combinatorial synthesis and evaluation of trialkyl galloyl amidoamine ionizable lipids for mRNA formulation. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 147(30), 26934–26943. https://doi.org/10.1021/jacs.5c09030
- Chicago author-date
- Golba, Bianka, Irene De Franceschi, Zifu Zhong, Martijn Schuijs, Claudia Mariela Brenis Gómez, Heleen Lauwers, Benoit Louage, et al. 2025. “Combinatorial Synthesis and Evaluation of Trialkyl Galloyl Amidoamine Ionizable Lipids for MRNA Formulation.” JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 147 (30): 26934–43. https://doi.org/10.1021/jacs.5c09030.
- Chicago author-date (all authors)
- Golba, Bianka, Irene De Franceschi, Zifu Zhong, Martijn Schuijs, Claudia Mariela Brenis Gómez, Heleen Lauwers, Benoit Louage, Iasona Sheshi, Nezha Badi, Bruno De Geest, and Filip Du Prez. 2025. “Combinatorial Synthesis and Evaluation of Trialkyl Galloyl Amidoamine Ionizable Lipids for MRNA Formulation.” JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 147 (30): 26934–26943. doi:10.1021/jacs.5c09030.
- Vancouver
- 1.Golba B, De Franceschi I, Zhong Z, Schuijs M, Brenis Gómez CM, Lauwers H, et al. Combinatorial synthesis and evaluation of trialkyl galloyl amidoamine ionizable lipids for mRNA formulation. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. 2025;147(30):26934–43.
- IEEE
- [1]B. Golba et al., “Combinatorial synthesis and evaluation of trialkyl galloyl amidoamine ionizable lipids for mRNA formulation,” JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 147, no. 30, pp. 26934–26943, 2025.
@article{01K6ABT82F8XJPR4PQ3N9FS0R4,
abstract = {{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.}},
author = {{Golba, Bianka and De Franceschi, Irene and Zhong, Zifu and Schuijs, Martijn and Brenis Gómez, Claudia Mariela and Lauwers, Heleen and Louage, Benoit and Sheshi, Iasona and Badi, Nezha and De Geest, Bruno and Du Prez, Filip}},
issn = {{0002-7863}},
journal = {{JOURNAL OF THE AMERICAN CHEMICAL SOCIETY}},
keywords = {{GALLIC ACID,SYSTEMS}},
language = {{eng}},
number = {{30}},
pages = {{26934--26943}},
title = {{Combinatorial synthesis and evaluation of trialkyl galloyl amidoamine ionizable lipids for mRNA formulation}},
url = {{http://doi.org/10.1021/jacs.5c09030}},
volume = {{147}},
year = {{2025}},
}
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