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Thioamides adjacent to the ionizable amine headgroup in ionizable lipids reduce the pKa of lipid nanoparticles and enhance mRNA transfection efficiency in vitro and in vivo

Yong Chen (UGent) , Emily De Lombaerde (UGent) , Aimee-Rose Bugler-Lamb (UGent) , Zifu Zhong (UGent) , Martijn Schuijs (UGent) , Claudia Mariela Brenis Gómez (UGent) , Jamie De Baere (UGent) , Mark Gontsarik (UGent) , Heleen Lauwers (UGent) , Kim Deswarte (UGent) , et al.
(2025) ANGEWANDTE CHEMIE-INTERNATIONAL EDITION.
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Abstract
Lipid nanoparticles (LNPs) are currently the most clinically advanced mRNA delivery vectors. However, optimizing LNPs for in vivo applications remains largely empirical. The apparent pKa of LNPs is a predictive factor for in vivo performance, with pKa values between 6 and 7 showing the highest efficacy. Despite this critical role of ionizable lipids in LNPs, the relationship between lipid structure and its influence on LNP pKa remains poorly studied. In this study, we report the design and the synthesis of a novel class of ionizable lipids featuring a thioamide moiety, enabling direct comparison between thioamide-containing (SAM) LNPs and amide-containing (OAM) LNPs. We find that substituting oxygen with sulfur in the amide group significantly decreases the apparent pKa of LNPs, increasing the likelihood of identifying lipids in combinatorial libraries that yield LNPs with a pKa in the desired 6-7 range. The reduction in pKa in LNPs containing SAM lipids, compared with OAM lipids, is attributed to the increased hydrophobicity of the thioamide group. Furthermore, by synthesizing multiple libraries of SAM lipids and varying the ionizable head group, alkyl chains, and linker length, we discovered thioamide lipids with distinct tissue tropism, including lipids that mediate splenic targeting by LNPs.
Keywords
ionizable lipid, pKa of LNP, thioamide, SIRNA, DELIVERY

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Citation

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MLA
Chen, Yong, et al. “Thioamides Adjacent to the Ionizable Amine Headgroup in Ionizable Lipids Reduce the PKa of Lipid Nanoparticles and Enhance MRNA Transfection Efficiency in Vitro and in Vivo.” ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2025, doi:10.1002/anie.202506954.
APA
Chen, Y., De Lombaerde, E., Bugler-Lamb, A.-R., Zhong, Z., Schuijs, M., Brenis Gómez, C. M., … De Geest, B. (2025). Thioamides adjacent to the ionizable amine headgroup in ionizable lipids reduce the pKa of lipid nanoparticles and enhance mRNA transfection efficiency in vitro and in vivo. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION. https://doi.org/10.1002/anie.202506954
Chicago author-date
Chen, Yong, Emily De Lombaerde, Aimee-Rose Bugler-Lamb, Zifu Zhong, Martijn Schuijs, Claudia Mariela Brenis Gómez, Jamie De Baere, et al. 2025. “Thioamides Adjacent to the Ionizable Amine Headgroup in Ionizable Lipids Reduce the PKa of Lipid Nanoparticles and Enhance MRNA Transfection Efficiency in Vitro and in Vivo.” ANGEWANDTE CHEMIE-INTERNATIONAL EDITION. https://doi.org/10.1002/anie.202506954.
Chicago author-date (all authors)
Chen, Yong, Emily De Lombaerde, Aimee-Rose Bugler-Lamb, Zifu Zhong, Martijn Schuijs, Claudia Mariela Brenis Gómez, Jamie De Baere, Mark Gontsarik, Heleen Lauwers, Kim Deswarte, Niek Sanders, Bart Lambrecht, Martin Guilliams, and Bruno De Geest. 2025. “Thioamides Adjacent to the Ionizable Amine Headgroup in Ionizable Lipids Reduce the PKa of Lipid Nanoparticles and Enhance MRNA Transfection Efficiency in Vitro and in Vivo.” ANGEWANDTE CHEMIE-INTERNATIONAL EDITION. doi:10.1002/anie.202506954.
Vancouver
1.
Chen Y, De Lombaerde E, Bugler-Lamb A-R, Zhong Z, Schuijs M, Brenis Gómez CM, et al. Thioamides adjacent to the ionizable amine headgroup in ionizable lipids reduce the pKa of lipid nanoparticles and enhance mRNA transfection efficiency in vitro and in vivo. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION. 2025;
IEEE
[1]
Y. Chen et al., “Thioamides adjacent to the ionizable amine headgroup in ionizable lipids reduce the pKa of lipid nanoparticles and enhance mRNA transfection efficiency in vitro and in vivo,” ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2025.
@article{01JXJ0ZEXQNVACCMSYWT0Z5N14,
  abstract     = {{Lipid nanoparticles (LNPs) are currently the most clinically advanced mRNA delivery vectors. However, optimizing LNPs for in vivo applications remains largely empirical. The apparent pKa of LNPs is a predictive factor for in vivo performance, with pKa values between 6 and 7 showing the highest efficacy. Despite this critical role of ionizable lipids in LNPs, the relationship between lipid structure and its influence on LNP pKa remains poorly studied. In this study, we report the design and the synthesis of a novel class of ionizable lipids featuring a thioamide moiety, enabling direct comparison between thioamide-containing (SAM) LNPs and amide-containing (OAM) LNPs. We find that substituting oxygen with sulfur in the amide group significantly decreases the apparent pKa of LNPs, increasing the likelihood of identifying lipids in combinatorial libraries that yield LNPs with a pKa in the desired 6-7 range. The reduction in pKa in LNPs containing SAM lipids, compared with OAM lipids, is attributed to the increased hydrophobicity of the thioamide group. Furthermore, by synthesizing multiple libraries of SAM lipids and varying the ionizable head group, alkyl chains, and linker length, we discovered thioamide lipids with distinct tissue tropism, including lipids that mediate splenic targeting by LNPs.}},
  author       = {{Chen, Yong and De Lombaerde, Emily and Bugler-Lamb, Aimee-Rose and Zhong, Zifu and Schuijs, Martijn and Brenis Gómez, Claudia Mariela and De Baere, Jamie and Gontsarik, Mark and Lauwers, Heleen and Deswarte, Kim and Sanders, Niek and Lambrecht, Bart and Guilliams, Martin and De Geest, Bruno}},
  issn         = {{1521-3773}},
  journal      = {{ANGEWANDTE CHEMIE-INTERNATIONAL EDITION}},
  keywords     = {{ionizable lipid,pKa of LNP,thioamide,SIRNA,DELIVERY}},
  language     = {{eng}},
  title        = {{Thioamides adjacent to the ionizable amine headgroup in ionizable lipids reduce the pKa of lipid nanoparticles and enhance mRNA transfection efficiency in vitro and in vivo}},
  url          = {{http://doi.org/10.1002/anie.202506954}},
  year         = {{2025}},
}
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