Isosteric 3D Bicyclo[1.1.1]Pentane\n(BCP) Core-Based\nLipids for mRNA Delivery and CRISPR/Cas Gene Editing

Lipid\nnanoparticles (LNPs) are an essential component\nof messenger\nRNA (mRNA) vaccines and genome editing therapeutics. Ionizable amino\nlipids, which play the most crucial role in enabling mRNA to overcome\ndelivery barriers, have, to date, been restricted to two-dimensional\n(2D) architectures. Inspired by improved physicochemical properties\nresulting from the incorporation of three-dimensionality (3D) into\nsmall-molecule drugs, we report the creation of 3D ionizable lipid\ndesigns through the introduction of bicyclo[1.1.1]pentane (BCP) core\nmotifs. BCP-based lipids enabled efficient <i>in vivo</i> mRNA delivery to the liver and spleen with significantly greater\nperformance over 2D benzene- and cyclohexane-based analogues. Notably,\nlead BCP-NC2-C12 LNPs mediated ∼90% reduction in the PCSK9\nserum protein level via CRISPR/Cas9 gene knockout, outperforming 2D\ncontrols and clinically used DLin-MC3-DMA LNPs at the same dose. Here,\nwe introduce BCP-based designs with superior <i>in vivo</i> activity, thereby expanding the chemical scope of ionizable amino\nlipids from 2D to 3D and offering a promising avenue to improve mRNA\nand gene editing efficiency for the continued development of genetic\nmedicines.