Branched endosomal disruptor (BEND) lipids mediate delivery of mRNA and CRISPR-Cas9 ribonucleoprotein complex for hepatic gene editing and T cell engineering

Lipid nanoparticles (LNPs) are the preeminent non-viral drug delivery vehicle for mRNA-based therapies. Immense effort has been placed on optimizing the ionizable lipid (IL) structure, which contains an amine core conjugated to lipid tails, as small molecular adjustments can result in substantial changes in the overall efficacy of the resulting LNPs. However, despite some advancements, a major barrier for LNP delivery is endosomal escape. Here, we develop a platform for synthesizing a class of branched ILs that improve endosomal escape. These compounds incorporate terminally branched groups that increase hepatic mRNA and ribonucleoprotein complex delivery and gene editing efficiency as well as T cell…

• NS
  National Science Foundation

  Awards: P30 CA016520, 1827457, CHE-1827457
• UO
  University of Pennsylvania

  Awards: P30 AI045008, P30 CA016520
• NI
  National Institutes of Health

  Awards: SCR_022380, P30 CA016520, AI045008, DP2TR002776, CA016520, P30 AI045008
• PS
  Perelman School of Medicine, University of Pennsylvania
• VI
  Vagelos Institute for Energy Science and Technology, University of Pennsylvania
• NI
  National Institute of Dental and Craniofacial Research

  Award: T90DE030854
• DO
  Division of Chemistry

  Awards: CHE-1827457, 1827457