The Extent to Which Lipid Nanoparticles Require Apolipoprotein E and Low-Density Lipoprotein Receptor for Delivery Changes with Ionizable Lipid Structure.
Kalina PaunovskaAlejandro J Da Silva SanchezMelissa P LokugamageDavid LoughreyElisa Schrader EcheverriAna CristianMarine Z C HatitPhilip J SantangeloKun ZhaoJames E DahlmanPublished in: Nano letters (2022)
Lipid nanoparticles (LNPs) have delivered therapeutic RNA to hepatocytes in humans. Adsorption of apolipoprotein E (ApoE) onto these clinical LNP-mRNA drugs has been shown to facilitate hepatocyte entry via the low-density lipoprotein receptor (LDLR). Since ApoE-LDLR trafficking is conserved in mice, non-human primates, and humans, characterizing this mechanism eased clinical transition. Recently, LNPs have delivered mRNA to non-hepatocytes in mice and non-human primates, suggesting they can target new cell types via ApoE- and LDLR-independent pathways. To test this hypothesis, we quantified how 60 LNPs delivered mRNA with cell type resolution in wild-type mice and three knockout mouse strains related to lipid trafficking: ApoE -/- , LDLR -/- , and PCSK9 -/- . These data suggest that the hydrophobic tail length of diketopiperazine-based lipids can be changed to drive ApoE- and LDLR-independent delivery in vivo . More broadly, the results support the hypothesis that endogenous LNP trafficking can be tuned by modifying lipid chemistry.
Keyphrases
- low density lipoprotein
- wild type
- cognitive decline
- high fat diet
- fatty acid
- endothelial cells
- high fat diet induced
- binding protein
- liver injury
- escherichia coli
- mild cognitive impairment
- induced pluripotent stem cells
- metabolic syndrome
- stem cells
- transcription factor
- single cell
- type diabetes
- drug induced
- adipose tissue
- insulin resistance
- single molecule
- bone marrow
- ionic liquid