Products Cited in Publications Worldwide Engineering Branched Ionizable Lipid for Hepatic Delivery of CRISPR/Cas9 Ribonucleoproteins

Engineering Branched Ionizable Lipid for Hepatic Delivery of CRISPR/Cas9 Ribonucleoproteins

Onuma, Haruno; Shimizu, Rina; Suzuki, Yuichi; Sato, Mina; Harashima, Hideyoshi; Sato, Yusuke

DOI:

Abstract

The delivery of the CRISPR/Cas ribonucleoprotein (RNP) has received attention for clinical applications owing to its high efficiency with few off-target effects. Lipid nanoparticles (LNPs) are potential non-viral vectors for the delivery of RNPs. Herein, we report the engineering of a branched scaffold structure of ionizable lipids for hepatic delivery of RNPs. Both the total carbon number and branching position were critical for the functional delivery of RNPs. The optimal ionizable lipid exhibited a more than 98% reduction in transthyretin protein after a single dose with no obvious signs of toxicity. Mechanistic study has revealed that optimal LNPs have a unique “flower-like structure” that depends on both the lipid structure and the payload and that these LNPs accumulate in hepatocytes in an apolipoprotein E-independent manner. These results represent a major step toward the realization of in vivo genome editing therapy via RNP delivery using chemically synthesizable LNP formulations.

Keywords

genome editing ; ribonucleoprotein ; lipid nanoparticles ; ionizable lipid ; scaffold ; liver

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ALC-0315

A13752122036272-55-497%

ALC-0315

140.0/25mg

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