Real‐Time pH‐Dependent Self‐Assembly of Ionisable Lipids from COVID‐19 Vaccines and In Situ Nucleic Acid Complexation - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Angewandte Chemie International Edition Année : 2023

Real‐Time pH‐Dependent Self‐Assembly of Ionisable Lipids from COVID‐19 Vaccines and In Situ Nucleic Acid Complexation

Haitao Yu
Angelina Angelova
Brendan Dyett
Lauren Matthews
  • Fonction : Auteur
Yiran Zhang
  • Fonction : Auteur
Mohamad El Mohamad
  • Fonction : Auteur
Xudong J Cai
  • Fonction : Auteur
Sepideh Valimehr
  • Fonction : Auteur
Calum J Drummond
Jiali Zhai

Résumé

Abstract Ionisable amino‐lipid is a key component in lipid nanoparticles (LNPs), which plays a crucial role in the encapsulation of RNA molecules, allowing efficient cellular uptake and then releasing RNA from acidic endosomes. Herein, we present direct evidence for the remarkable structural transitions, with decreasing membrane curvature, including from inverse micellar, to inverse hexagonal, to two distinct inverse bicontinuous cubic, and finally to a lamellar phase for the two mainstream COVID‐19 vaccine ionisable ALC‐0315 and SM‐102 lipids, occurring upon gradual acidification as encountered in endosomes. The millisecond kinetic growth of the inverse cubic and hexagonal structures and the evolution of the ordered structural formation upon ionisable lipid‐RNA/DNA complexation are quantitatively revealed by in situ synchrotron radiation time‐resolved small angle X‐ray scattering coupled with rapid flow mixing. We found that the final self‐assembled structural identity, and the formation kinetics, were controlled by the ionisable lipid molecular structure, acidic bulk environment, lipid compositions, and nucleic acid molecular structure/size. The implicated link between the inverse membrane curvature of LNP and LNP endosomal escape helps future optimisation of ionisable lipids and LNP engineering for RNA and gene delivery.

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Chimie
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hal-04293710 , version 1 (19-11-2023)

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Paternité - Pas d'utilisation commerciale - Pas de modification

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Haitao Yu, Angelina Angelova, Borislav Angelov, Brendan Dyett, Lauren Matthews, et al.. Real‐Time pH‐Dependent Self‐Assembly of Ionisable Lipids from COVID‐19 Vaccines and In Situ Nucleic Acid Complexation. Angewandte Chemie International Edition, 2023, 62 (35), pp.e202304977. ⟨10.1002/anie.202304977⟩. ⟨hal-04293710⟩
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