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

Author

Listed:
  • Marshall S. Padilla

    (University of Pennsylvania)

  • Kaitlin Mrksich

    (University of Pennsylvania)

  • Yiming Wang

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Rebecca M. Haley

    (University of Pennsylvania)

  • Jacqueline J. Li

    (University of Pennsylvania)

  • Emily L. Han

    (University of Pennsylvania)

  • Rakan El-Mayta

    (University of Pennsylvania
    Universidade do Porto)

  • Emily H. Kim

    (University of Pennsylvania)

  • Sofia Dias

    (University of Pennsylvania
    Universidade do Porto
    Universidade do Porto
    Universidade do Porto)

  • Ningqiang Gong

    (University of Pennsylvania)

  • Sridatta V. Teerdhala

    (University of Pennsylvania)

  • Xuexiang Han

    (University of Pennsylvania)

  • Vivek Chowdhary

    (University of Pennsylvania)

  • Lulu Xue

    (University of Pennsylvania)

  • Zain Siddiqui

    (University of Pennsylvania)

  • Hannah M. Yamagata

    (University of Pennsylvania)

  • Dongyoon Kim

    (University of Pennsylvania)

  • Il-Chul Yoon

    (University of Pennsylvania)

  • James M. Wilson

    (University of Pennsylvania)

  • Ravi Radhakrishnan

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Michael J. Mitchell

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

Abstract

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 transfection compared to non-branched lipids. Through an array of complementary experiments, we determine that our lipid architecture induces greater endosomal penetration and disruption. This work provides a scheme to generate a class of ILs for both mRNA and protein delivery.

Suggested Citation

  • Marshall S. Padilla & Kaitlin Mrksich & Yiming Wang & Rebecca M. Haley & Jacqueline J. Li & Emily L. Han & Rakan El-Mayta & Emily H. Kim & Sofia Dias & Ningqiang Gong & Sridatta V. Teerdhala & Xuexian, 2025. "Branched endosomal disruptor (BEND) lipids mediate delivery of mRNA and CRISPR-Cas9 ribonucleoprotein complex for hepatic gene editing and T cell engineering," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55137-6
    DOI: 10.1038/s41467-024-55137-6
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    References listed on IDEAS

    as
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