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Peer-reviewedCC BYNano Letters

Lipid Nanoparticle Protein Coronas Arise through Lipoprotein Fusion Rather Than Shell-like Adsorption

  • Shaun Grumelot1
  • Naseeha Mohammed2
  • Ghafar Yerima3
  • Jorge A. Colón-Rosado1
  • Seyed Amirhossein Sadeghi1
  • Fei Fang1
  • Kylie Hilsen1
  • Brooke Shango2,1
  • Amir Ata Saei4
  • Amanda M. Murray5
  • Michael J. Mitchell5
  • Babak Borhan1
5 more authors
  • Liangliang Sun1
  • Hojatollah Vali6
  • Mohammad R. K. Mofrad3
  • Kathryn A. Whitehead2
  • Morteza Mahmoudi1
6 affiliations
  1. 1Michigan State University , , , ,
  2. 2Carnegie Mellon University , , , ,
  3. 3University of California Berkeley , , , ,
  4. 4Karolinska Institute , , ,
  5. 5University of Pennsylvania , , , ,
  6. 6McGill University , , , ,
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Abstract

The protein corona influences the in vivo biodistribution of ionizable lipid nanoparticles (LNPs) in nucleic acid delivery, yet their structural architecture remains poorly defined. Using cryo-transmission electron microscopy, we visualized LNP-protein interactions in their native state. We show that, unlike the discrete "fuzzy" shells observed on hard nanoparticles, LNPs displayed no peripheral protein shell. Instead, controlled incubation and competitive "dual-particle" assays, supported by molecular dynamics simulations, indicate that LNP membranes undergo localized thickening and electron-dense remodeling consistent with lipoprotein integration rather than surface adsorption. Similar features were observed in extracellular vesicles, suggesting that this behavior is shared among lipid-based carriers, and proteomic analysis identified apolipoproteins as the dominant associated proteins. Together, these findings support a model in which the biological identity of LNPs arises through membrane remodeling rather than shell-like adsorption and provide a framework for the rational design of targeted nanomedicines.

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Cite

BibTeXRIS
BibTeX
@article{grumelot2026lipid,
  title = {{Lipid Nanoparticle Protein Coronas Arise through Lipoprotein Fusion Rather Than Shell-like Adsorption}},
  author = {Shaun Grumelot and Naseeha Mohammed and Ghafar Yerima and Jorge A. Colón-Rosado and Seyed Amirhossein Sadeghi and Fei Fang and Kylie Hilsen and Brooke Shango and Amir Ata Saei and Amanda M. Murray and Michael J. Mitchell and Babak Borhan and Liangliang Sun and Hojatollah Vali and Mohammad R. K. Mofrad and Kathryn A. Whitehead and Morteza Mahmoudi},
  journal = {Nano Letters},
  year = {2026},
  month = aug,
  doi = {10.1021/acs.nanolett.6c00689},
  url = {https://doi.org/10.1021/acs.nanolett.6c00689},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Lipid Nanoparticle Protein Coronas Arise through Lipoprotein Fusion Rather Than Shell-like Adsorption
AU  - Shaun Grumelot
AU  - Naseeha Mohammed
AU  - Ghafar Yerima
AU  - Jorge A. Colón-Rosado
AU  - Seyed Amirhossein Sadeghi
AU  - Fei Fang
AU  - Kylie Hilsen
AU  - Brooke Shango
AU  - Amir Ata Saei
AU  - Amanda M. Murray
AU  - Michael J. Mitchell
AU  - Babak Borhan
AU  - Liangliang Sun
AU  - Hojatollah Vali
AU  - Mohammad R. K. Mofrad
AU  - Kathryn A. Whitehead
AU  - Morteza Mahmoudi
PY  - 2026
DA  - 2026/08/11
JO  - Nano Letters
DO  - 10.1021/acs.nanolett.6c00689
UR  - https://doi.org/10.1021/acs.nanolett.6c00689
AB  - The protein corona influences the in vivo biodistribution of ionizable lipid nanoparticles (LNPs) in nucleic acid delivery, yet their structural architecture remains poorly defined. Using cryo-transmission electron microscopy, we visualized LNP-protein interactions in their native state. We show that, unlike the discrete "fuzzy" shells observed on hard nanoparticles, LNPs displayed no peripheral protein shell. Instead, controlled incubation and competitive "dual-particle" assays, supported by molecular dynamics simulations, indicate that LNP membranes undergo localized thickening and electron-dense remodeling consistent with lipoprotein integration rather than surface adsorption. Similar features were observed in extracellular vesicles, suggesting that this behavior is shared among lipid-based carriers, and proteomic analysis identified apolipoproteins as the dominant associated proteins. Together, these findings support a model in which the biological identity of LNPs arises through membrane remodeling rather than shell-like adsorption and provide a framework for the rational design of targeted nanomedicines.
SN  - 1530-6984
SN  - 1530-6992
ER  -