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Peer-reviewedCC BY-NC-NDNature Communications

Influence of protein aggregates, extracellular vesicles, and lipoprotein fusion on ionizable lipid nanoparticles protein corona analysis

  • Babak Borhan1
  • Amanda M. Murray2
  • Amir Ata Saei3
  • Bahareh Ghaffari4
  • James E. Jackson4
  • Naseeha Mohammed5
  • Michael J. Mitchell6,7,8,2,9,10,11
  • Hojatollah Vali12,13
  • Kathryn A. Whitehead14,15
  • Morteza Mahmoudi16,17
17 affiliations
  1. 1Department of Chemistry, Michigan State University, East Lansing, MI, 48824, USA. [email protected]
  2. 2Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, 19104, USA
  3. 3Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, 171 77, Sweden
  4. 4Department of Chemistry, Michigan State University, East Lansing, MI, 48824, USA
  5. 5Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA
  6. 6Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
  7. 7Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
  8. 8Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
  9. 9Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
  10. 10Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
  11. 11Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
  12. 12Department of Anatomy and Cell Biology, McGill University, Montreal, QC, H3A 0C7, Canada
  13. 13Facility for Electron Microscopy Research, McGill University, Montreal, QC, H3A 0C7, Canada
  14. 14Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. [email protected]
  15. 15Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. [email protected]
  16. 16Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, 48823, USA. [email protected]
  17. 17Precision Health Program, Michigan State University, East Lansing, MI, 48823, USA. [email protected]
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Abstract

Since 2018, ionizable lipid nanoparticles (LNPs) have revolutionized nucleic acid therapeutics. However, achieving potent extrahepatic delivery remains a formidable challenge, primarily due to rapid hepatic uptake driven by apolipoprotein adsorption. While analyzing the LNP protein corona is essential for engineering organ-specific tropism, these soft materials present unique analytical hurdles. Co-isolation of blood-borne contaminants, such as extracellular vesicles and lipoproteins, often masks the true corona composition. This perspective examines the critical need for refined proteomic strategies to distinguish genuine corona proteins from impurities. We propose tailored investigative approaches, suggesting the LNP protein corona significantly differs from the rigid shells observed on inorganic nanoparticles. Engineering organ-specific LNPs requires a deep understanding of the protein corona, yet its fluid nature makes analysis difficult. This perspective identifies how blood contaminants mask true corona composition and advocates for refined strategies to study these unique lipid-protein interfaces.

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Cite

BibTeXRIS
BibTeX
@article{borhan2026influence,
  title = {{Influence of protein aggregates, extracellular vesicles, and lipoprotein fusion on ionizable lipid nanoparticles protein corona analysis}},
  author = {Babak Borhan and Amanda M. Murray and Amir Ata Saei and Bahareh Ghaffari and James E. Jackson and Naseeha Mohammed and Michael J. Mitchell and Hojatollah Vali and Kathryn A. Whitehead and Morteza Mahmoudi},
  journal = {Nature Communications},
  year = {2026},
  month = jun,
  doi = {10.1038/s41467-026-74240-4},
  url = {https://doi.org/10.1038/s41467-026-74240-4},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Influence of protein aggregates, extracellular vesicles, and lipoprotein fusion on ionizable lipid nanoparticles protein corona analysis
AU  - Babak Borhan
AU  - Amanda M. Murray
AU  - Amir Ata Saei
AU  - Bahareh Ghaffari
AU  - James E. Jackson
AU  - Naseeha Mohammed
AU  - Michael J. Mitchell
AU  - Hojatollah Vali
AU  - Kathryn A. Whitehead
AU  - Morteza Mahmoudi
PY  - 2026
DA  - 2026/06/12
JO  - Nature Communications
DO  - 10.1038/s41467-026-74240-4
UR  - https://doi.org/10.1038/s41467-026-74240-4
AB  - Since 2018, ionizable lipid nanoparticles (LNPs) have revolutionized nucleic acid therapeutics. However, achieving potent extrahepatic delivery remains a formidable challenge, primarily due to rapid hepatic uptake driven by apolipoprotein adsorption. While analyzing the LNP protein corona is essential for engineering organ-specific tropism, these soft materials present unique analytical hurdles. Co-isolation of blood-borne contaminants, such as extracellular vesicles and lipoproteins, often masks the true corona composition. This perspective examines the critical need for refined proteomic strategies to distinguish genuine corona proteins from impurities. We propose tailored investigative approaches, suggesting the LNP protein corona significantly differs from the rigid shells observed on inorganic nanoparticles. Engineering organ-specific LNPs requires a deep understanding of the protein corona, yet its fluid nature makes analysis difficult. This perspective identifies how blood contaminants mask true corona composition and advocates for refined strategies to study these unique lipid-protein interfaces.
SN  - 2041-1723
ER  -