Lipoprotein Corona Reshapes the Internal Structure of Lipid Nanoparticles
Year: 2026
Authors: Caselli L., Rojas-Rodriguez M., Pacciani V., Calamai M., Frigerio R., Zendrini A., Sanita G., Esposito E., Leung A., Wacklin-Knecht H., Humphreys B., Arosio P., Cardellini J., Berti D.
Autors Affiliation: Univ Florence, Dept Chem Ugo Schiff, I-50019 Florence, Italy; Ctr Colloid & Surface Sci, CSGI, I-50019 Florence, Italy; European Lab Nonlinear Spect, I-50019 Sesto Fiorentino, Italy; Natl Inst Opt, Natl Res Council, I-50019 Florence, Italy; Swiss Fed Inst Technol, Inst Chem & Bioengn, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland; CNR, Inst Appl Sci & Intelligent Syst, EYE Lab, I-80131 Naples, Italy; European Spallat Source ERIC, SE-22100 Lund, Sweden; Inst Laue Langevin, F-38042 Grenoble, 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.
Journal/Review: ACS NANO
Volume: 20 (36) Pages from: 24915 to: 24933
More Information: The authors wish to acknowledge Luca Casettari and Mattia Tiboni (Department of Biomolecular Sciences, University of Urbino, Urbino, Italy) for the design and fabrication of the microfluidic chip used for the preparation of LCNPs. This research was funded by the Italian Ministry of University and Research under Ministerial Decree D.D. No. 937 of 06/03/2026-FIS 3 Call (Project FIS-2024-00672, entitled: Engineering Phase-Separated Lipid Nanoparticles with Enhanced Endosomal Escape and Organ-Targeted Delivery via Lipoprotein Hybridization, CUP B53C26001260001). This work has been supported also by the European Community through the BOW Project (H2020-EIC-FETPROACT2019, ID 952183) and by PRIN 2022 PNRR: Lipid Nanovectors for the Delivery of Nucleic Acids: a Composition-Structure-Function Relationship Approach (Lancelot)-P2022RBF5P-CUP B53D23025810001-Finanziato dall’Unione europea-Next Generation EU-Missione 4, Componente 2, Investimento 1.1-Avviso MUR D.D. 1409 del 14/09/2022. The authors also acknowledge MUR-Italy (Progetto Dipartimenti di Eccellenza 2018-2022, ref B96C1700020008 and Dipartimenti di Eccellenza 2023-2027 (DICUS 2.0) allocated to the Department of Chemistry Ugo Schiff). The authors acknowledge cofunding from the European Union – NextGenerationEU programme in the context of the National Recovery and Resilience Plan, Mission 4, Component 2, Investment 1.4, CN00000041, CN3 National Center for Gene Therapy and Drugs based on RNA Technology-Spoke 5 Inflammatory and Infectious Diseases, CUP: B13C22001010001. The authors thank the Elettra Sincrotrone Trieste (Trieste, Italy) for (Proposal No. 20247105, Austrian SAXS beamline), the European Synchrotron Radiation Facility (ESRF) (Proposal No. CH-7517, Beamline ID02), and the Diamond Light Source (Proposal No. SM43918 on B21) for SAXS beamtime provision, the Institut Laue-Langevin (Grenoble, France) for NR beamtime (9-10-1874). The authors also thank PROGETTO CIR01_00023-IMPARA-Imaging Dalle Molecole Alla Preclinica Rafforzamento Del Capitale Umano CUP B28I20000150001 and National Recovery and Resilience Plan (NRRP), Project Cascata-MNESYS (PE0000006)-A multiscalei ntegrated approach to the study of nervous system in health and disease (DN. 1553 11.10.2022). The synthesis of dGMO was carried out at the DEMAX Platform, resulting from proposals 320410 and 75387, at the European Spallation Source ERIC. The persistent identifier for the samples is 10.5281/zenodo.14959335.KeyWords: lipid nanoparticles; lipoproteins; biomolecular corona; liquid crystalline lipid nanoparticles; lipid exchange; structural remodelingDOI: 10.1021/acsnano.6c09400
