Chemical topology of lipo-amino fatty acid mRNA carriers triggers distinct lipid bulk phases and endosomal escape mechanisms☆
6 affiliations
- 1Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Munich 81377, Germany
- 2Faculty of Physics, Ludwig-Maximilians University, Geschwister-Scholl-Platz 1, Munich, Germany
- 3Pharmaceutical Technology and Biopharmaceutics, Department of Pharmacy, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Munich 81377, Germany
- 4Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, Munich 80799, Germany
- 5Comprehensive Pneumology Center (CPC-M), Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research (DZL), Munich 81377, Germany
- 6Pharmaceutical Engineering and Technology Research Scientists (PETRS), Germany
Abstract
LAF-Stp xenopeptides (XPs) comprising lipoamino fatty acid (LAF) units connected with the tetraethylene pentamine derived polyamino acid Stp were identified as a novel class of amphiphilic mRNA carriers. A ‘chameleon-like’ polarity switch is observed upon transition from neutral physiological to endosomal acidic pH. Protonation of the lipidic tertiary amine of LAF results in an ~2 log unit change in the octanol/water partition coefficient (logD), consistent with all-atom molecular dynamics simulations. mRNA delivery efficacy is tunable by the chemical topology (either a flexible ‘U-shape’ or a constrained ‘Bundle’ structure) and specific modifications in the LAF-Stp linker domains. Specifically, replacing lysine with shorter ornithine linkers further increases the structural rigidity of Bundles. For all LAF-XPs, protonation-induced solubilization of carriers triggers endosomal destabilization (evidenced by galectin-8 recruitment) and successful cytosolic mRNA transfection. Carriers with U-shape topology strongly depend on endosomal acidification, as demonstrated by an up to ~20-fold drop in efficacy upon treatment with v-ATPase inhibitor bafilomycin, similar as found for the ionizable polymer polyethylenimine. In contrast, Bundles are far less affected (<4-fold reduction) by bafilomycin treatment. Small-angle X-ray scattering (SAXS) reveals that lipid bulk phase structures are largely pH-independent for both topologies. Interestingly, U-shapes form lamellar phases, whereas Bundle topology induces non-lamellar bicontinuous phases with negative membrane curvature. These findings suggest distinct endosomal escape mechanisms for Bundle and U-shapes. Both carriers benefit from endosomal protonation and solubilization, but only Bundles can adopt pH-independent membrane-destabilizing fusogenic phases, reflected by faster kinetics and characteristic cellular morphology in a galectin-8 assay.
Related
- Metal-Based Anticancer Drugs: Integrating Pharmaceutical Perspectives with DFT-Based Quantum Chemical Topology (QTAIM and ELF)
- S-nitrosylation topology in melanoma: established mechanisms, unresolved redox-immune links, and a testable framework
- Chemical Mechanisms of Cerebral Ischemia–Reperfusion Injury and Neuroprotection in the Thrombectomy Era
- β-arrestin1 directly engages Gαs to sustain endosomal GPCR signaling
- Chemokine CXCL12 Mediates Transcription Factor HSF1-Dependent Small Extracellular Vesicle Secretion Through Different Endosomal Stages
BibTeX
@article{grau2026chemical,
title = {{Chemical topology of lipo-amino fatty acid mRNA carriers triggers distinct lipid bulk phases and endosomal escape mechanisms☆}},
author = {Melina Grau and Ekaterina Kostyurina and Johanna Seidl and Nora Martini and Benjamin Winkeljann and Olivia M. Merkel and Joachim O. Rädler and Ernst Wagner},
journal = {Materials Today (Kidlington, England)},
year = {2026},
month = aug,
doi = {10.1016/j.mattod.2026.103353},
url = {https://europepmc.org/article/PMC/PMC7619666},
note = {CC BY},
}
RIS
TY - JOUR
TI - Chemical topology of lipo-amino fatty acid mRNA carriers triggers distinct lipid bulk phases and endosomal escape mechanisms☆
AU - Melina Grau
AU - Ekaterina Kostyurina
AU - Johanna Seidl
AU - Nora Martini
AU - Benjamin Winkeljann
AU - Olivia M. Merkel
AU - Joachim O. Rädler
AU - Ernst Wagner
PY - 2026
DA - 2026/08/01
JO - Materials Today (Kidlington, England)
DO - 10.1016/j.mattod.2026.103353
UR - https://europepmc.org/article/PMC/PMC7619666
AB - LAF-Stp xenopeptides (XPs) comprising lipoamino fatty acid (LAF) units connected with the tetraethylene pentamine derived polyamino acid Stp were identified as a novel class of amphiphilic mRNA carriers. A ‘chameleon-like’ polarity switch is observed upon transition from neutral physiological to endosomal acidic pH. Protonation of the lipidic tertiary amine of LAF results in an ~2 log unit change in the octanol/water partition coefficient (logD), consistent with all-atom molecular dynamics simulations. mRNA delivery efficacy is tunable by the chemical topology (either a flexible ‘U-shape’ or a constrained ‘Bundle’ structure) and specific modifications in the LAF-Stp linker domains. Specifically, replacing lysine with shorter ornithine linkers further increases the structural rigidity of Bundles. For all LAF-XPs, protonation-induced solubilization of carriers triggers endosomal destabilization (evidenced by galectin-8 recruitment) and successful cytosolic mRNA transfection. Carriers with U-shape topology strongly depend on endosomal acidification, as demonstrated by an up to ~20-fold drop in efficacy upon treatment with v-ATPase inhibitor bafilomycin, similar as found for the ionizable polymer polyethylenimine. In contrast, Bundles are far less affected (<4-fold reduction) by bafilomycin treatment. Small-angle X-ray scattering (SAXS) reveals that lipid bulk phase structures are largely pH-independent for both topologies. Interestingly, U-shapes form lamellar phases, whereas Bundle topology induces non-lamellar bicontinuous phases with negative membrane curvature. These findings suggest distinct endosomal escape mechanisms for Bundle and U-shapes. Both carriers benefit from endosomal protonation and solubilization, but only Bundles can adopt pH-independent membrane-destabilizing fusogenic phases, reflected by faster kinetics and characteristic cellular morphology in a galectin-8 assay.
SN - 1369-7021
SN - 1873-4103
ER -