Improving peptide-based lipids for safer and more effective mRNA delivery in living organisms for gene editing and protein therapy

A lead compound (Dab4) was identified that minimizes hepatotoxicity while maintaining superior delivery performance.

• Peptide ionizable lipids (PILs) consist of three components: a building block, side-chain length, and a hydrophobic tail.
• Systematic optimization of PIL structures led to the identification of Dab4, which has four building blocks and a moderate side chain length.
• Tail chemistry of Dab4-derived PILs influenced organ targeting, with the B12-a13Dab4 variant showing optimal performance in the liver.
• The B12-a13Dab4 lipid nanoparticle (LNP) demonstrated significantly higher liver delivery efficiency and improved biosafety compared to the FDA-approved SM-102 formulation.
• B12-a13Dab4 LNP effectively triggered in vivo prime editing and achieved significant therapeutic effects in a model of Hereditary Tyrosinemia Type 1 by co-delivering specific mRNAs.

Simplified