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bioRxiv · 10.64898/2025.12.21.695162

Lipid nanoparticle protein coronas form via lipoprotein fusion rather than shell-like adsorption

Grumelot, S.·Mohammed, N.·Colonrosado, J.·Sadeghi, S. A.·Fang, F.·Hilsen, K.·Shango, B.·Saei, A. A.·Murray, A. M.·Mitchell, M. J.·Borhan, B.·Sun, L.·Vali, H.·Whitehead, K.·Mahmoudi, M.
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Abstract

The protein corona influences the in vivo biodistribution of ionizable lipid nanoparticles (LNPs) in nucleic acid delivery, yet its 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 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. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/695162v2_ufig1.gif" ALT="Figure 1"> View larger version (79K): org.highwire.dtl.DTLVardef@a6f2b2org.highwire.dtl.DTLVardef@879d12org.highwire.dtl.DTLVardef@159196dorg.highwire.dtl.DTLVardef@945749_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Grumelot, S., Mohammed, N., Colonrosado, J., Sadeghi, S. A., Fang, F., Hilsen, K., Shango, B., Saei, A. A., Murray, A. M., Mitchell, M. J., Borhan, B., Sun, L., Vali, H., Whitehead, K., Mahmoudi, M.. 2025-12-23. Lipid nanoparticle protein coronas form via lipoprotein fusion rather than shell-like adsorption. https://doi.org/10.64898/2025.12.21.695162

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