In vivo delivery of plasmid DNA by lipid nanoparticles: the influence of ionizable cationic lipids on organ-selective gene expression

📖 Top 20% JournalApr 27, 2022Biomaterials science

How Ionizable Lipids in Fat Nanoparticles Affect Organ-Targeted Gene Delivery Using Plasmid DNA

AI simplified

mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Lipid nanoparticles containing DLin-KC2-DMA achieved higher plasmid DNA transfection efficiency compared to DLin-MC3-DMA and DODAP.

Different ionizable cationic lipids show varying effectiveness in gene expression for plasmid DNA delivery.
DLin-KC2-DMA led to greater pDNA transfection compared to both DLin-MC3-DMA and DODAP.
Lipid nanoparticles formulated with DLin-KC2-DMA or DLin-MC3-DMA resulted in significantly higher protein production in the spleen than in the liver.
The choice of ionizable cationic lipid and nucleic acid cargo is important for organ-selective gene expression.

AI simplified

Ionizable cationic lipids play a critical role in developing new gene therapies for various biomedical applications, including COVID-19 vaccines. However, it remains unclear whether the formulation of lipid nanoparticles (LNPs) using DLin-MC3-DMA, an optimized ionizable lipid clinically used for small interfering RNA (siRNA) therapy, also facilitates high liver-selective transfection of other gene therapies such as plasmid DNA (pDNA). Here we report the first investigation into pDNA transfection efficiency in different mouse organs after intramuscular and intravenous administration of lipid nanoparticles (LNPs) where DLin-MC3-DMA, DLin-KC2-DMA or DODAP are used as the ionizable cationic lipid component of the LNP. We discovered that these three benchmark lipids previously developed for siRNA delivery followed an unexpected characteristic rank order in gene expression efficiency when utilized for pDNA. In particular, DLin-KC2-DMA facilitated higherpDNA transfection than DLin-MC3-DMA and DODAP, possibly due to its head group pand lipid tail structure. Interestingly, LNPs formulated with either DLin-KC2-DMA or DLin-MC3-DMA exhibited significantly higherprotein production in the spleen than in the liver. This work sheds light on the importance of the choice of ionizable cationic lipid and nucleic acid cargo for organ-selective gene expression. The study also provides a new design principle towards the formulation of more effective LNPs for biomedical applications of pDNA, such as gene editing, vaccines and immunotherapies. in vivo K in vivo a

Full Text

Full text is available at the source.

View full text ↗

Abstract

Full Text

Related papers