{
  "abstract": "mRNA-based gene editing therapeutics offer the potential to permanently cure diseases but are hindered by suboptimal delivery platforms. Here, we devise a robust combinatorial chemistry for the plug-and-play assembly of structurally diverse biodegradable ionizable lipids from amines/thiols and dialkyl maleates. After screening 500 ionizable lipids, we obtained structure-activity relationships essential for effective in vitro mRNA delivery with the help of machine learning. Furthermore, we identified a lead ionizable lipid candidate that produced potent lipid nanoparticles for the delivery of various gene editing tools in wild-type and genetically modified mice compared to literature and industry benchmark lipid nanoparticles. Mechanistically, our lipid nanoparticles show favorable physicochemical properties, which could synergistically contribute to the superior delivery performance. This study highlights the utility of this synthetic method as well as the generality of this platform for potent in vivo gene editing.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Bioengineering, University of Pennsylvania",
    "State Key Laboratory of RNA Innovation, Science and Engineering, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences",
    "Shanghai Institute of Biochemistry and Cell Biology",
    "Department of Medicine, University of Pennsylvania",
    "Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania",
    "School of Pharmacy, East China Normal University",
    "East China Normal University",
    "Division of Pediatric General, Thoracic, and Fetal Surgery, The Center for Fetal Research, Children’s Hospital of Philadelphia",
    "University of Pennsylvania",
    "Department of Biomedical Engineering, Duke University",
    "Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania",
    "University of Pennsylvania Perelman School of Medicine",
    "UNIVERSITY OF PENNSYLVANIA",
    "Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania",
    "Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania",
    "Center for Precision Engineering for Health, University of Pennsylvania",
    "Institute for Immunology, Perelman School of Medicine, University of Pennsylvania",
    "Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Xuexiang Han",
      "orcid": "0000-0003-0011-5222"
    },
    {
      "affs": [
        3,
        4,
        5,
        6
      ],
      "name": "Ying Xu",
      "orcid": "0000-0001-7341-8676"
    },
    {
      "affs": [
        0,
        7,
        8
      ],
      "name": "Adele S. Ricciardi",
      "orcid": "0000-0003-2637-8522"
    },
    {
      "affs": [
        0,
        8
      ],
      "name": "Junchao Xu",
      "orcid": "0000-0003-0725-8111"
    },
    {
      "affs": [
        9,
        8
      ],
      "name": "Yan Xiang"
    },
    {
      "affs": [
        0,
        7,
        8
      ],
      "name": "Rohan Palanki",
      "orcid": "0000-0001-5168-5634"
    },
    {
      "affs": [
        10,
        8
      ],
      "name": "Vivek Chowdhary",
      "orcid": "0000-0003-1277-0128"
    },
    {
      "affs": [
        0,
        8
      ],
      "name": "Lulu Xue",
      "orcid": "0000-0001-5719-1336"
    },
    {
      "affs": [
        0,
        8
      ],
      "name": "Ningqiang Gong",
      "orcid": "0000-0002-9444-8505"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Mohamad‐Gabriel Alameh",
      "orcid": "0000-0002-5672-6930"
    },
    {
      "affs": [
        7,
        11
      ],
      "name": "William H. Peranteau",
      "orcid": "0000-0003-1608-861X"
    },
    {
      "affs": [
        10,
        11
      ],
      "name": "James M. Wilson",
      "orcid": "0000-0002-9630-3131"
    },
    {
      "affs": [
        9,
        12
      ],
      "name": "Daniel Reker",
      "orcid": "0000-0003-4789-7380"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Drew Weissman",
      "orcid": "0000-0002-1501-6510"
    },
    {
      "affs": [
        13,
        14,
        15,
        0,
        16,
        17,
        4
      ],
      "name": "Michael J. Mitchell",
      "orcid": "0000-0002-3628-2244"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1vsdtr9nvr9sq.bib",
  "cited_by": 14,
  "doi": "10.1073/pnas.2528144123",
  "fulltext_url": null,
  "id": "1vsdtr9nvr9sq",
  "issns": [
    "0027-8424",
    "1091-6490"
  ],
  "landing_url": "https://doi.org/10.1073/pnas.2528144123",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|RNA Interference and Gene Delivery"
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  "openalex": "W4408077221",
  "pdf_url": null,
  "pmcid": "PMC11888472",
  "pmid": "40060499",
  "published": "2026-05-26",
  "publisher": "National Academy of Sciences",
  "ris": "https://research.draconitic.com/paper/1vsdtr9nvr9sq.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:46Z",
      "native_id": "W4408077221",
      "source": "openalex",
      "url": "https://doi.org/10.1073/pnas.2528144123"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|RNA Interference and Gene Delivery",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Plug-and-play assembly of biodegradable ionizable lipids for potent mRNA delivery and gene editing in vivo",
  "title_text": "Plug-and-play assembly of biodegradable ionizable lipids for potent mRNA delivery and gene editing in vivo",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T13:20:28Z",
  "url": "https://research.draconitic.com/paper/1vsdtr9nvr9sq",
  "venue": "Proceedings of the National Academy of Sciences",
  "versions": []
}