{
  "abstract": "Active targeting can improve the efficacy of mRNA therapeutics, but ligand-mediated targeting with lipid nanoparticles (LNPs) remains challenging. Here, we studied the impact of polyethylene glycol (PEG)-lipid composition and triantennary N-acetylgalactosamine (TriGalNAc)-modification on the hepatic delivery efficiency of mRNA-LNPs. Incorporating TriGalNAc-lipid into LNPs containing dimyristoyl glycerol (DMG)-PEG2000 or distearoylphosphatidylethanolamine (DSPE)-PEG2000, excipients used in FDA-approved RNA-LNPs or liposomes, did not further improve hepatic mRNA delivery. We discovered that incorporating TriGalNAc-lipid into LNPs containing DSPE-PEG350 increased hepatic luciferase expression 4-6-fold over TriGalNAc-conjugated or unconjugated DMG-PEG2000 LNPs, and 60-fold over TriGalNAc-conjugated or unconjugated DSPE-PEG2000 LNPs in vivo. Despite its relatively low molecular weight PEG, unconjugated DSPE-PEG350 LNP showed moderately extended blood circulation but only moderately reduced cellular uptake in vitro, potentially providing a balanced platform for adding TriGalNAc ligands and improving the overall hepatic delivery efficiency in vivo. The pairing of TriGalNAc-lipid and DSPE-PEG350 in LNPs containing adenine base editor RNAs against PCSK9 lowered plasma cholesterol in wild-type mice, while conventional DMG-PEG2000 LNP was ineffective at the same dose. This study highlights the importance of redesigning the LNP surface to potentiate ligand-mediated active targeting to the liver.",
  "abstract_shown": true,
  "affiliations": [
    "Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland21231, United States.",
    "Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland21231, United States.",
    "Department of Physiology, Pharmacology & Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland21231, United States.",
    "Department of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland21205, United States.",
    "Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland21231, United States.",
    "Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland21231, United States.",
    "Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland21231, United States.",
    "Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland21231, United States.",
    "Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland21231, United States."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Saed Abbasi",
      "orcid": "0000-0001-8874-233X"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Kimberly M Bockley"
    },
    {
      "affs": [
        3
      ],
      "name": "Johannes Dohr"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Emily Chen"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Davell M Carter"
    },
    {
      "affs": [
        1
      ],
      "name": "Cynthia A Berlinicke"
    },
    {
      "affs": [
        5,
        6,
        7
      ],
      "name": "Xizhen Lian",
      "orcid": "0009-0001-4329-3734"
    },
    {
      "affs": [
        3
      ],
      "name": "Maria Viskadourou"
    },
    {
      "affs": [
        3
      ],
      "name": "Emma Burke"
    },
    {
      "affs": [
        0,
        1,
        2,
        4,
        8
      ],
      "name": "Laura M Ensign"
    },
    {
      "affs": [
        3,
        6,
        8
      ],
      "name": "Gregory A Newby"
    },
    {
      "affs": [
        0,
        1,
        2,
        4,
        6,
        8
      ],
      "name": "Justin Hanes"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/21j980cb3hmyx.bib",
  "cited_by": 0,
  "doi": "10.1021/acsnano.6c10855",
  "fulltext_url": "https://europepmc.org/articles/PMC13602997",
  "id": "21j980cb3hmyx",
  "issns": [
    "1936-0851",
    "1936-086X"
  ],
  "landing_url": "https://europepmc.org/article/MED/42916086",
  "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": [
    [
      "openalex",
      "1312|RNA Interference and Gene Delivery"
    ]
  ],
  "openalex": "W7211977430",
  "pdf_url": "https://europepmc.org/articles/PMC13602997?pdf=render",
  "pmcid": "PMC13602997",
  "pmid": "42916086",
  "published": "2026-09-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/21j980cb3hmyx.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:02Z",
      "native_id": "MED:42916086",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42916086"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|RNA Interference and Gene Delivery",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Boosting Ligand-Mediated Hepatic mRNA Delivery and Gene Editing Through Coordinated Pairing of Polyethylene Glycol-Modified Lipids.",
  "title_text": "Boosting Ligand-Mediated Hepatic mRNA Delivery and Gene Editing Through Coordinated Pairing of Polyethylene Glycol-Modified Lipids.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:21:02Z",
  "url": "https://research.draconitic.com/paper/21j980cb3hmyx",
  "venue": "ACS nano",
  "versions": []
}