Branched endosomal disruptor (BEND) lipids mediate delivery of mRNA and CRISPR-Cas9 ribonucleoprotein complex for hepatic gene editing and T cell engineering
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 subst...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55137-6 |
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| author | 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 Michael J. Mitchell |
| author_facet | 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 Michael J. Mitchell |
| author_sort | Marshall S. Padilla |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a75439f6733b4f3f9a9cda7f6f310cf5 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a75439f6733b4f3f9a9cda7f6f310cf52025-01-26T12:40:45ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-024-55137-6Branched endosomal disruptor (BEND) lipids mediate delivery of mRNA and CRISPR-Cas9 ribonucleoprotein complex for hepatic gene editing and T cell engineeringMarshall S. Padilla0Kaitlin Mrksich1Yiming Wang2Rebecca M. Haley3Jacqueline J. Li4Emily L. Han5Rakan El-Mayta6Emily H. Kim7Sofia Dias8Ningqiang Gong9Sridatta V. Teerdhala10Xuexiang Han11Vivek Chowdhary12Lulu Xue13Zain Siddiqui14Hannah M. Yamagata15Dongyoon Kim16Il-Chul Yoon17James M. Wilson18Ravi Radhakrishnan19Michael J. Mitchell20Department of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaGene Therapy Program, Perelman School of Medicine, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaGene Therapy Program, Perelman School of Medicine, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Science, University of PennsylvaniaAbstract 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.https://doi.org/10.1038/s41467-024-55137-6 |
| spellingShingle | 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 Michael J. Mitchell Branched endosomal disruptor (BEND) lipids mediate delivery of mRNA and CRISPR-Cas9 ribonucleoprotein complex for hepatic gene editing and T cell engineering Nature Communications |
| title | Branched endosomal disruptor (BEND) lipids mediate delivery of mRNA and CRISPR-Cas9 ribonucleoprotein complex for hepatic gene editing and T cell engineering |
| title_full | Branched endosomal disruptor (BEND) lipids mediate delivery of mRNA and CRISPR-Cas9 ribonucleoprotein complex for hepatic gene editing and T cell engineering |
| title_fullStr | Branched endosomal disruptor (BEND) lipids mediate delivery of mRNA and CRISPR-Cas9 ribonucleoprotein complex for hepatic gene editing and T cell engineering |
| title_full_unstemmed | Branched endosomal disruptor (BEND) lipids mediate delivery of mRNA and CRISPR-Cas9 ribonucleoprotein complex for hepatic gene editing and T cell engineering |
| title_short | Branched endosomal disruptor (BEND) lipids mediate delivery of mRNA and CRISPR-Cas9 ribonucleoprotein complex for hepatic gene editing and T cell engineering |
| title_sort | branched endosomal disruptor bend lipids mediate delivery of mrna and crispr cas9 ribonucleoprotein complex for hepatic gene editing and t cell engineering |
| url | https://doi.org/10.1038/s41467-024-55137-6 |
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