A Systematic Study of Unsaturation in Lipid Nanoparticles Leads to Improved mRNA Transfection In Vivo

DOI Web Site Web Site 被引用文献3件
  • Sang M. Lee
    Department of Biochemistry University of Texas Southwestern Medical Center 5323 Harry Hines Blvd. Dallas TX 75390-9038 USA
  • Qiang Cheng
    Department of Biochemistry University of Texas Southwestern Medical Center 5323 Harry Hines Blvd. Dallas TX 75390-9038 USA
  • Xueliang Yu
    Department of Biochemistry University of Texas Southwestern Medical Center 5323 Harry Hines Blvd. Dallas TX 75390-9038 USA
  • Shuai Liu
    Department of Biochemistry University of Texas Southwestern Medical Center 5323 Harry Hines Blvd. Dallas TX 75390-9038 USA
  • Lindsay T. Johnson
    Department of Biochemistry University of Texas Southwestern Medical Center 5323 Harry Hines Blvd. Dallas TX 75390-9038 USA
  • Daniel J. Siegwart
    Department of Biochemistry University of Texas Southwestern Medical Center 5323 Harry Hines Blvd. Dallas TX 75390-9038 USA

説明

<jats:title>Abstract</jats:title><jats:p>Lipid nanoparticles (LNPs) represent the leading concept for mRNA delivery. Unsaturated lipids play important roles in nature with potential for mRNA therapeutics, but are difficult to access through chemical synthesis. To systematically study the role of unsaturation, modular reactions were utilized to access a library of 91 amino lipids, enabled by the synthesis of unsaturated thiols. An ionizable lipid series (4A3) emerged from in vitro and in vivo screening, where the 4A3 core with a citronellol‐based (Cit) periphery emerged as best. We studied the interaction between LNPs and a model endosomal membrane where 4A3‐Cit demonstrated superior lipid fusion over saturated lipids, suggesting its unsaturated tail promotes endosomal escape. Furthermore, 4A3‐Cit significantly improved mRNA delivery efficacy in vivo through Selective ORgan Targeting (SORT), resulting in 18‐fold increased protein expression over parent LNPs. These findings provide insight into how lipid unsaturation promotes mRNA delivery and demonstrate how lipid mixing can enhance efficacy.</jats:p>

収録刊行物

被引用文献 (3)*注記

もっと見る

問題の指摘

ページトップへ