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Peer-reviewedCC BYACS nano

Boosting Ligand-Mediated Hepatic mRNA Delivery and Gene Editing Through Coordinated Pairing of Polyethylene Glycol-Modified Lipids.

  • Saed Abbasi1,2
  • Kimberly M Bockley1,3
  • Johannes Dohr4
  • Emily Chen1,5
  • Davell M Carter1,3
  • Cynthia A Berlinicke2
  • Xizhen Lian6,7,8
  • Maria Viskadourou4
  • Emma Burke4
  • Laura M Ensign1,2,3,5,9
  • Gregory A Newby4,7,9
  • Justin Hanes1,2,3,5,7,9
9 affiliations
  1. 1Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland21231, United States.
  2. 2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland21231, United States.
  3. 3Department of Physiology, Pharmacology & Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland21231, United States.
  4. 4Department of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland21205, United States.
  5. 5Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland21231, United States.
  6. 6Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland21231, United States.
  7. 7Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland21231, United States.
  8. 8Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland21231, United States.
  9. 9Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland21231, United States.
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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.

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Cite

BibTeXRIS
BibTeX
@article{abbasi2026boosting,
  title = {{Boosting Ligand-Mediated Hepatic mRNA Delivery and Gene Editing Through Coordinated Pairing of Polyethylene Glycol-Modified Lipids.}},
  author = {Saed Abbasi and Kimberly M Bockley and Johannes Dohr and Emily Chen and Davell M Carter and Cynthia A Berlinicke and Xizhen Lian and Maria Viskadourou and Emma Burke and Laura M Ensign and Gregory A Newby and Justin Hanes},
  journal = {ACS nano},
  year = {2026},
  month = sep,
  doi = {10.1021/acsnano.6c10855},
  url = {https://europepmc.org/article/MED/42916086},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Boosting Ligand-Mediated Hepatic mRNA Delivery and Gene Editing Through Coordinated Pairing of Polyethylene Glycol-Modified Lipids.
AU  - Saed Abbasi
AU  - Kimberly M Bockley
AU  - Johannes Dohr
AU  - Emily Chen
AU  - Davell M Carter
AU  - Cynthia A Berlinicke
AU  - Xizhen Lian
AU  - Maria Viskadourou
AU  - Emma Burke
AU  - Laura M Ensign
AU  - Gregory A Newby
AU  - Justin Hanes
PY  - 2026
DA  - 2026/09/01
JO  - ACS nano
DO  - 10.1021/acsnano.6c10855
UR  - https://europepmc.org/article/MED/42916086
AB  - 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.
SN  - 1936-0851
SN  - 1936-086X
ER  -