Lipoprotein Corona Reshapes the Internal Structure of Lipid Nanoparticles.
8 affiliations
- 1Department of Chemistry "Ugo Schiff", University of Florence, 50019Sesto Fiorentino, Florence, Italy.
- 2CSGI, Center for Colloid and Surface Science, 50019Sesto Fiorentino, Florence, Italy.
- 3European Laboratory for Non-Linear Spectroscopy, Via Nello Carrara 1, 50019Sesto Fiorentino, Italy.
- 4National Institute of Optics─National Research Council, Via Nello Carrara 1-I, 50019Sesto-Fiorentino, Firenze, Italia.
- 5ETH Zürich, Department of Chemistry and Applied Biosciences, Institute for Chemical and Bioengineering, 8093Zürich, Switzerland.
- 6EYE-Lab, Institute of Applied Sciences and Intelligent Systems, National Research Council, Via Pietro Castellino 111, 80131Napoli, Italy.
- 7European Spallation Source ERIC, P.O. Box 176, SE 22100Lund, Sweden.
- 8Institut Laue-Langevin, 71 Avenue des Martyrs, CS20156, 38042Grenoble, France.
Abstract
Lipid nanoparticles (LNPs) are central to nanomedicine, yet their clinical translation is limited by the difficulty of predicting structure-bioactivity relationships. Although the biomolecular corona is known to define the nanoparticle biological identity by modifying surface properties, its effect on internal nanoparticle organization remains largely unexplored. Since the internal lipid organization of LNPs governs key properties, including stability, cargo protection, internalization and intracellular trafficking, understanding this coupling is critical to correlate synthetic design to therapeutic outcome. Here, combining structural and mechanistic evidence, we show that plasma lipoproteins engage in molecular-scale lipid exchange with the LCNP membrane, rather than persisting as an adsorbed layer of intact particles, actively remodeling the internal nanoparticle structure. Using model lipid liquid-crystalline nanoparticles with well-defined cubic and inverse hexagonal phases, we systematically investigate how lipoproteins modulate LNP structure. Combining fluorescence nanoparticle tracking, synchrotron small-angle X-ray scattering, cryo-electron microscopy, and neutron reflectometry with isotopic contrast matching, we provide evidence of lipoprotein-driven lipid transfer and phase reorganization at the nanoscale. We observe a phase-selective response: inverse hexagonal LNPs remain structurally stable despite lipid exchange, whereas cubic LNPs undergo pronounced remodeling, including significant change in size and lattice ordering. These transformations correlate with distinct cellular uptake profiles. Our findings suggest that in soft lipid nanoparticles, the biological identity commonly described as a biomolecular corona is not merely a surface event but an interface-mediated process that reshapes the nanoparticle internal structure, with direct implications for next-generation nanomedicine design.
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BibTeX
@article{caselli2026lipoprotein,
title = {{Lipoprotein Corona Reshapes the Internal Structure of Lipid Nanoparticles.}},
author = {Lucrezia Caselli and Marta Rojas-Rodríguez and Valentina Pacciani and Martino Calamai and Roberto Frigerio and Andrea Zendrini and Gennaro Sanità and Emanuela Esposito and Anna Leung and Hanna Wacklin-Knecht and Ben Humphreys and Paolo Arosio and Jacopo Cardellini and Debora Berti},
journal = {ACS nano},
year = {2026},
month = sep,
doi = {10.1021/acsnano.6c09400},
url = {https://europepmc.org/article/MED/42915048},
note = {CC BY},
}
RIS
TY - JOUR
TI - Lipoprotein Corona Reshapes the Internal Structure of Lipid Nanoparticles.
AU - Lucrezia Caselli
AU - Marta Rojas-Rodríguez
AU - Valentina Pacciani
AU - Martino Calamai
AU - Roberto Frigerio
AU - Andrea Zendrini
AU - Gennaro Sanità
AU - Emanuela Esposito
AU - Anna Leung
AU - Hanna Wacklin-Knecht
AU - Ben Humphreys
AU - Paolo Arosio
AU - Jacopo Cardellini
AU - Debora Berti
PY - 2026
DA - 2026/09/01
JO - ACS nano
DO - 10.1021/acsnano.6c09400
UR - https://europepmc.org/article/MED/42915048
AB - Lipid nanoparticles (LNPs) are central to nanomedicine, yet their clinical translation is limited by the difficulty of predicting structure-bioactivity relationships. Although the biomolecular corona is known to define the nanoparticle biological identity by modifying surface properties, its effect on internal nanoparticle organization remains largely unexplored. Since the internal lipid organization of LNPs governs key properties, including stability, cargo protection, internalization and intracellular trafficking, understanding this coupling is critical to correlate synthetic design to therapeutic outcome. Here, combining structural and mechanistic evidence, we show that plasma lipoproteins engage in molecular-scale lipid exchange with the LCNP membrane, rather than persisting as an adsorbed layer of intact particles, actively remodeling the internal nanoparticle structure. Using model lipid liquid-crystalline nanoparticles with well-defined cubic and inverse hexagonal phases, we systematically investigate how lipoproteins modulate LNP structure. Combining fluorescence nanoparticle tracking, synchrotron small-angle X-ray scattering, cryo-electron microscopy, and neutron reflectometry with isotopic contrast matching, we provide evidence of lipoprotein-driven lipid transfer and phase reorganization at the nanoscale. We observe a phase-selective response: inverse hexagonal LNPs remain structurally stable despite lipid exchange, whereas cubic LNPs undergo pronounced remodeling, including significant change in size and lattice ordering. These transformations correlate with distinct cellular uptake profiles. Our findings suggest that in soft lipid nanoparticles, the biological identity commonly described as a biomolecular corona is not merely a surface event but an interface-mediated process that reshapes the nanoparticle internal structure, with direct implications for next-generation nanomedicine design.
SN - 1936-0851
SN - 1936-086X
ER -