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

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, Xuexiang Han, Vivek Chowdhary, Lulu Xue, Zain Siddiqui, Hannah M. Yamagata, Dongyoon Kim, Il-Chul Yoon, James M. Wilson, Ravi Radhakrishnan and Michael J. Mitchell ()
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Marshall S. Padilla: University of Pennsylvania
Kaitlin Mrksich: University of Pennsylvania
Yiming Wang: 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
Emily H. Kim: University of Pennsylvania
Sofia Dias: University of Pennsylvania
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
Michael J. Mitchell: University of Pennsylvania

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55137-6

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