Lipid nanoparticle mRNA systems containing high levels of sphingomyelin engender higher protein expression in hepatic and extra-hepatic tissues

• DOI: 10.1016/j.omtm.2023.06.005
• Publication Date: 2023-06-12T06:25:29Z
• Authors: Nisha Chander; Genc Basha; Miffy Hok Yan Cheng; Dominik Witzigmann; Pieter R. Cullis
• Keywords: splenocytes; bone marrow; QH573-671; mRNA; Genetics; hepatocytes; Original Article; lipid nanoparticles; QH426-470; Cytology; helper lipids

Lipid nanoparticles (LNPs) for delivery of mRNA usually contain ionizable lipid/helper lipid/cholesterol/PEG-lipid in molar ratios 50:10:38.5:1.5, respectively. These LNPs are rapidly cleared from the circulation following intravenous (i.v.) administration, limiting uptake into other tissues. Here, we investigate properties LNP systems prepared with high levels "helper" lipids such as 1,2-distearoyl-sn-glycero-3-phosphorylcholine (DSPC) or N-(hexadecanoyl)-sphing-4-enine-1-phosphocholine (egg sphingomyelin [ESM]). We show that mRNAs containing 40 mol % DSPC ESM have a unique morphology small interior "solid" core situated an aqueous compartment is bounded by lipid bilayer. The encapsulated exhibits enhanced stability presence serum. exhibit significantly improved transfection vitro compared 10 ESM. When injected i.v., extended lifetimes DSPC, resulting accumulation extrahepatic Systems result gene expression spleen and bone marrow well liver post i.v. injection mRNAs. conclude helper provide new approach transfecting hepatic tissues.Graphical abstract