Lipid Nanoparticle Surface Engineering with Heparosan Polysaccharides Enhances mRNA Efficacy via Reduced Endosomal Retention.
7 affiliations
- 1Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, Oklahoma73019, United States.
- 2Department of Pathology, University of Oklahoma Health Campus, Oklahoma City, Oklahoma73104, United States.
- 3Department of Biochemistry and Physiology, University of Oklahoma Health Campus, Oklahoma City, Oklahoma73104, United States.
- 4Stephenson Cancer Center, University of Oklahoma, Oklahoma City, Oklahoma73104, United States.
- 5Institute for Biomedical Engineering, Science, and Technology (IBEST), University of Oklahoma, Norman, Oklahoma73019, United States.
- 6Harold Hamm Diabetes Center, University of Oklahoma, Oklahoma City, Oklahoma73104, United States.
- 7Materials Science and Engineering Program, University of Oklahoma, Norman, Oklahoma73019, United States.
Abstract
In this study, we developed a library of mRNA lipid nanoparticles (LNPs) containing clinically used ionizable lipids. We surface-modified these nanoparticles with heparosan polysaccharides and systematically compared their performance with conventional poly(ethylene glycol) (PEG)-modified formulations. Our heparosan (HEP)-coated LNPs increased mRNA expression in dendritic and macrophage cell lines by up to ∼10-fold. Mechanistic studies using live-cell imaging and intracellular nanoparticle trafficking analysis revealed that HEP-modified LNPs exhibited reduced colocalization with late endosomal (Rab7+) and lysosomal (LAMP1+) compartments. These findings are consistent with enhanced endosomal escape of HEP-modified formulations. Repeated subcutaneous administrations of HEP-modified firefly luciferase mRNA-LNPs demonstrated sustained expression and distinct response dynamics in mice. We further observed significantly enhanced humoral anti-spike protein immune responses in mice after subcutaneous administration of HEP-modified LNPs containing SARS-CoV-2 spike S-2P mRNA. Histopathological evaluation and spleen immune cell profiling showed no observable toxicity or adverse effects. Overall, these results demonstrate the effects of HEP surface modification on mRNA LNP expression, intracellular trafficking, and in vivo activity, and support HEP-based surface engineering as a PEG-free approach for nucleic acid delivery and potential future applications in nanomedicine.
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BibTeX
@article{he2026lipid,
title = {{Lipid Nanoparticle Surface Engineering with Heparosan Polysaccharides Enhances mRNA Efficacy via Reduced Endosomal Retention.}},
author = {Yuxin He and Lin Wang and Abigael P Williams and Trisha I Valerio and Yuanhong Sun and James Bowman and Samantha D Ricketts and Savannah Hammond and Aidan Sison and Jezan Alexandre and Zachary Niastor and Wei R Chen and Dixy E Green and Kar-Ming Fung and Paul L DeAngelis and Stefan Wilhelm},
journal = {ACS nano},
year = {2026},
month = oct,
doi = {10.1021/acsnano.6c11865},
url = {https://europepmc.org/article/MED/42915664},
note = {CC BY},
}
RIS
TY - JOUR
TI - Lipid Nanoparticle Surface Engineering with Heparosan Polysaccharides Enhances mRNA Efficacy via Reduced Endosomal Retention.
AU - Yuxin He
AU - Lin Wang
AU - Abigael P Williams
AU - Trisha I Valerio
AU - Yuanhong Sun
AU - James Bowman
AU - Samantha D Ricketts
AU - Savannah Hammond
AU - Aidan Sison
AU - Jezan Alexandre
AU - Zachary Niastor
AU - Wei R Chen
AU - Dixy E Green
AU - Kar-Ming Fung
AU - Paul L DeAngelis
AU - Stefan Wilhelm
PY - 2026
DA - 2026/10/01
JO - ACS nano
DO - 10.1021/acsnano.6c11865
UR - https://europepmc.org/article/MED/42915664
AB - In this study, we developed a library of mRNA lipid nanoparticles (LNPs) containing clinically used ionizable lipids. We surface-modified these nanoparticles with heparosan polysaccharides and systematically compared their performance with conventional poly(ethylene glycol) (PEG)-modified formulations. Our heparosan (HEP)-coated LNPs increased mRNA expression in dendritic and macrophage cell lines by up to ∼10-fold. Mechanistic studies using live-cell imaging and intracellular nanoparticle trafficking analysis revealed that HEP-modified LNPs exhibited reduced colocalization with late endosomal (Rab7+) and lysosomal (LAMP1+) compartments. These findings are consistent with enhanced endosomal escape of HEP-modified formulations. Repeated subcutaneous administrations of HEP-modified firefly luciferase mRNA-LNPs demonstrated sustained expression and distinct response dynamics in mice. We further observed significantly enhanced humoral anti-spike protein immune responses in mice after subcutaneous administration of HEP-modified LNPs containing SARS-CoV-2 spike S-2P mRNA. Histopathological evaluation and spleen immune cell profiling showed no observable toxicity or adverse effects. Overall, these results demonstrate the effects of HEP surface modification on mRNA LNP expression, intracellular trafficking, and in vivo activity, and support HEP-based surface engineering as a PEG-free approach for nucleic acid delivery and potential future applications in nanomedicine.
SN - 1936-0851
SN - 1936-086X
ER -