Formulation and characterization of novel ionizable and cationic lipid nanoparticles for the delivery of splice‐switching oligonucleotides
Author(s)
Type
Journal Article
Abstract
Despite increasing knowledge about the mechanistic aspects of lipid nanoparticles (LNPs) as oligonucleotide carriers, the structure-function relationship in LNPs has been generally overlooked. Understanding this correlation is critical in the rational design of LNPs. Here, a materials characterization approach is utilized, applying structural information from small-angle X-ray scattering experiments to design novel LNPs focusing on distinct lipid organizations with a minimal compositional variation. The lipid phase structures are characterized in these LNPs and their corresponding bulk lipid mixtures with small-angle scattering techniques, and the LNP-cell interactions in vitro with respect to cytotoxicity, hemolysis, cargo delivery, cell uptake, and lysosomal swelling. An LNP is identified that outperforms Onpattro lipid composition using lipid components and molar ratios which differ from the gold standard clinical LNPs. The base structure of these LNPs has an inverse micellar phase organization, whereas the LNPs with inverted hexagonal phases are not functional, suggesting that this phase formation may not be needed for LNP-mediated oligonucleotide delivery. The importance of stabilizer choice for the LNP function is demonstrated and super-resolution microscopy highlights the complexity of the delivery mechanisms, where lysosomal swelling for the majority of LNPs is observed. This study highlights the importance of advanced characterization for the rational design of LNPs to enable the study of structure-function relationships.
Date Issued
2025-04-28
Date Acceptance
2025-02-26
Citation
Advanced Materials, 2025, 37 (17)
ISSN
0935-9648
Publisher
Wiley
Start Page
e2419538
Journal / Book Title
Advanced Materials
Volume
37
Issue
17
Copyright Statement
© 2025 The Author(s). Advanced Materials published by Wiley-VCH GmbH This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40091434
Subjects
drug delivery
lipid nanoparticle
oligonucleotide
small angle scattering
stochastic optical reconstruction microscopy
Publication Status
Published
Coverage Spatial
Germany
Article Number
2419538
Date Publish Online
2025-03-16