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Nucleic Acid-Loaded Lipid Nanoparticle Interactions with Model Endosomal Membranes. | LitMetric

Nucleic Acid-Loaded Lipid Nanoparticle Interactions with Model Endosomal Membranes.

ACS Appl Mater Interfaces

Advanced Drug Delivery, Pharmaceutical Sciences, AstraZeneca R&D, Macclesfield SK10 2NA, U.K.

Published: July 2022

AI Article Synopsis

  • * The research found that lipid insertion into membranes is most effective at pH 6.5 and 5.5, while at higher pH levels, LNPs are more likely to bind intact rather than fuse, highlighting the role of pH in LNP fusion during cell entry.
  • * Additionally, LNPs with mRNA deliver more nucleic acids than those with Poly(A) cargo, suggesting that researchers can optimize LNPs for better delivery based on the type of nucleic acid

Article Abstract

Lipid nanoparticles (LNPs) are important delivery systems for RNA-based therapeutics, yet the mechanism of their interaction with endosomal membranes remains unclear. Here, the interactions of nucleic acid-loaded LNPs that contain an ionizable lipid with models of the early and late endosomal membranes are studied, for the first time, using different reflectometry techniques. Novel insight is provided with respect to the subphase pH, the stage of the endosome, and the nature of the nucleic acid cargo. It is found that the insertion of lipids from the LNPs into the model membrane is greatest at pH 6.5 and 5.5, whereas at higher pH, lipid insertion is suppressed with evidence instead for the binding of intact LNPs, demonstrating the importance of the pH in the fusion of LNPs undergoing the endosomal pathway. Furthermore, and independently of the pH, the effect of the early- versus late-stage endosomal models is minimal, suggesting that the increased fluidity and anionic nature of the late endosome has little effect on the extent of LNP interaction. Last, there is greater nucleic acid delivery from LNPs containing mRNA than Poly(A), indicating that the extent of interaction can be tuned according to the nature of the nucleic acid cargo. Such new information on the relative impact of factors influencing nucleic acid delivery by LNP interactions with endosomal membranes is important in the design and tuning of vehicles with improved nucleic acid delivery capacities.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9264317PMC
http://dx.doi.org/10.1021/acsami.2c06065DOI Listing

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