{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Munich 81377, Germany",
    "Faculty of Physics, Ludwig-Maximilians University, Geschwister-Scholl-Platz 1, Munich, Germany",
    "Pharmaceutical Technology and Biopharmaceutics, Department of Pharmacy, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Munich 81377, Germany",
    "Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, Munich 80799, Germany",
    "Comprehensive Pneumology Center (CPC-M), Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research (DZL), Munich 81377, Germany",
    "Pharmaceutical Engineering and Technology Research Scientists (PETRS), Germany"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Melina Grau"
    },
    {
      "affs": [
        1
      ],
      "name": "Ekaterina Kostyurina",
      "orcid": "0000-0002-5696-2378"
    },
    {
      "affs": [
        0
      ],
      "name": "Johanna Seidl"
    },
    {
      "affs": [
        2
      ],
      "name": "Nora Martini",
      "orcid": "0009-0005-2562-8157"
    },
    {
      "affs": [
        2,
        3,
        4,
        5
      ],
      "name": "Benjamin Winkeljann"
    },
    {
      "affs": [
        2,
        3,
        4
      ],
      "name": "Olivia M. Merkel",
      "orcid": "0000-0002-4151-3916"
    },
    {
      "affs": [
        1,
        3
      ],
      "name": "Joachim O. Rädler"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Ernst Wagner",
      "orcid": "0000-0001-8413-0934"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/c4rk9kejpy6x1.bib",
  "cited_by": 2,
  "doi": "10.1016/j.mattod.2026.103353",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7619666/?tool=EBI",
  "id": "c4rk9kejpy6x1",
  "issns": [
    "1369-7021",
    "1873-4103"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC7619666",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1312|RNA Interference and Gene Delivery"
    ]
  ],
  "openalex": "W7156361783",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7619666/pdf/?tool=EBI",
  "pmcid": "PMC7619666",
  "pmid": "42967105",
  "published": "2026-08-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/c4rk9kejpy6x1.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T15:20:28Z",
      "native_id": "PMC:PMC7619666",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC7619666"
    },
    {
      "first_seen": "2026-11-03T12:23:01Z",
      "native_id": "PMC7619666",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.mattod.2026.103353"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|RNA Interference and Gene Delivery",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Chemical topology of lipo-amino fatty acid mRNA carriers triggers distinct lipid bulk phases and endosomal escape mechanisms☆",
  "title_text": "Chemical topology of lipo-amino fatty acid mRNA carriers triggers distinct lipid bulk phases and endosomal escape mechanisms☆",
  "type": "peer-reviewed",
  "updated_at": "2026-11-04T12:20:42Z",
  "url": "https://research.draconitic.com/paper/c4rk9kejpy6x1",
  "venue": "Materials Today (Kidlington, England)",
  "versions": []
}