Acidic pH-induced changes in lipid nanoparticle membrane packing.
Kyoka Koitabashi1, Hiroki Nagumo1, Mizuka Nakao1
1School of Pharmacy, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo 108-8641, Japan.
Biochimica Et Biophysica Acta. Biomembranes
|April 26, 2021
Summary
Lipid nanoparticles (LNPs) with ionizable cationic lipids show reduced membrane packing at acidic pH, facilitating endosomal escape for nucleic acid delivery. This property enhances the efficiency of small interfering RNA (siRNA) delivery for gene silencing applications.
Area of Science:
- Biochemistry
- Materials Science
- Cell Biology
Background:
- Lipid nanoparticles (LNPs) are crucial for delivering nucleic acids into cells.
- Endosomal escape is a critical step for cytosolic delivery of encapsulated cargo.
- The physicochemical properties of LNPs, particularly their interaction with endosomes, influence delivery efficiency.
Purpose of the Study:
- To investigate the pH-dependent physicochemical changes in lipid nanoparticles (LNPs) containing ionizable cationic lipids.
- To understand how these changes facilitate the release of encapsulated nucleic acids into the cell cytosol.
- To correlate LNP properties with the efficiency of gene silencing using small interfering RNA (siRNA).
Main Methods:
- Preparation of LNPs incorporating an ionizable cationic lipid.
- Measurement of laurdan generalized polarization values to assess lipid membrane packing and hydration.
- Evaluation of pH-induced variations in LNP properties based on the percentage of ionizable cationic lipids.
- Assessment of siRNA delivery and gene knockdown efficiency (β-galactosidase) in cells.
Main Results:
- Decreased pH led to reduced laurdan generalized polarization values, indicating decreased lipid membrane packing and increased hydration.
- The pH-induced changes in LNP properties were more pronounced with higher percentages of ionizable cationic lipids.
- Reduced lipid packing at acidic pH suggests a transition towards non-bilayer structures, promoting LNP-endosome fusion.
- siRNA delivery and β-galactosidase knockdown efficiency increased with the ratio of a specific ionizable lipid (KC2).
Conclusions:
- Acidic pH destabilizes the lipid packing in LNPs containing ionizable cationic lipids, promoting endosomal escape.
- The findings elucidate the mechanism of LNP-mediated nucleic acid release, crucial for optimizing gene therapy vectors.
- These insights aid in the rational design of LNPs for enhanced cytosolic delivery and therapeutic efficacy.
