Acidification-Induced Structure Evolution of Lipid Nanoparticles Correlates with Their <i>In Vitro</i> Gene Transfections.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 36608273.
- Also identified by DOI 10.1021/acsnano.2c06213 and PMC identifier 9878718.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The rational design of lipid nanoparticles (LNPs) for enhanced gene delivery remains challenging because of incomplete knowledge of their formulation-structure relationship that impacts their intracellular behavior and consequent function. Small-angle neutron scattering has been used in this work to investigate the structure of LNPs encapsulating plasmid DNA upon their acidification (from pH 7.4 to 4.0), as would be encountered during endocytosis. The results revealed the acidification-induced structure evolution (AISE) of the LNPs on different dimension scales, involving protonation of the ionizable lipid, volume expansion and redistribution of aqueous and lipid components. A similarity analysis using an LNP's structural feature space showed a strong positive correlation between function (measured by intracellular luciferase expression) and the extent of AISE, which was further enhanced by the fraction of unsaturated helper lipid. Our findings reveal molecular and nanoscale changes occurring during AISE that underpin the LNPs' formulation-nanostructure-function relationship, aiding the rational design of application-directed gene delivery vehicles.