The Extent to Which Lipid Nanoparticles Require Apolipoprotein E and Low-Density Lipoprotein Receptor for Delivery Changes with Ionizable Lipid Structure.
basic_science · Level V
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- Record sourced from PubMed, PMID 36521071.
- Also identified by DOI 10.1021/acs.nanolett.2c03741.
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Abstract
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<sup>-/-</sup>, LDLR<sup>-/-</sup>, and PCSK9<sup>-/-</sup>. These data suggest that the hydrophobic tail length of diketopiperazine-based lipids can be changed to drive ApoE- and LDLR-independent delivery <i>in vivo</i>. More broadly, the results support the hypothesis that endogenous LNP trafficking can be tuned by modifying lipid chemistry.
Medical subject headings
- Apolipoproteins E
- Lipoproteins, LDL
- Nanoparticles