Protein corona formed on lipid nanoparticles compromises delivery efficiency of mRNA cargo

Elizabeth Voke, Mariah L. Arral, Henry J. Squire, Teng-Jui Lin, Lining Zheng, Roxana Coreas, Alison Lui, Anthony T. Iavarone, Rebecca L. Pinals (), Kathryn A. Whitehead () and Markita P. Landry ()
Additional contact information
Elizabeth Voke: Berkeley
Mariah L. Arral: Carnegie Mellon University
Henry J. Squire: Berkeley
Teng-Jui Lin: Berkeley
Lining Zheng: Berkeley
Roxana Coreas: Berkeley
Alison Lui: Berkeley
Anthony T. Iavarone: Berkeley
Rebecca L. Pinals: Massachusetts Institute of Technology
Kathryn A. Whitehead: Carnegie Mellon University
Markita P. Landry: Berkeley

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Lipid nanoparticles (LNPs) are the most clinically advanced nonviral RNA-delivery vehicles, though challenges remain in fully understanding how LNPs interact with biological systems. In vivo, proteins form an associated corona on LNPs that redefines their physicochemical properties and influences delivery outcomes. Despite its importance, the LNP protein corona is challenging to study owing to the technical difficulty of selectively recovering soft nanoparticles from biological samples. Herein, we develop a quantitative, label-free mass spectrometry-based proteomics approach to characterize the protein corona on LNPs. Critically, this protein corona isolation workflow avoids artifacts introduced by the presence of endogenous nanoparticles in human biofluids. We apply continuous density gradient ultracentrifugation for protein-LNP complex isolation, with mass spectrometry for protein identification normalized to protein composition in the biofluid alone. With this approach, we quantify proteins consistently enriched in the LNP corona including vitronectin, C-reactive protein, and alpha-2-macroglobulin. We explore the impact of these corona proteins on cell uptake and mRNA expression in HepG2 human liver cells, and find that, surprisingly, increased levels of cell uptake do not correlate with increased mRNA expression in part due to protein corona-induced lysosomal trafficking of LNPs. Our results underscore the need to consider the protein corona in the design of LNP-based therapeutics.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-63726-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63726-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-63726-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().