In Vivo RNA Delivery to Hematopoietic Stem and Progenitor Cells via Targeted Lipid Nanoparticles
Ex vivo autologous hematopoietic stem cell (HSC) gene therapy has provided new therapies for the treatment of hematological disorders. However, these therapies have several limitations owing to the manufacturing complexities and toxicity resulting from required conditioning regimens. Here, we develo...
| Main Authors: | , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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American Chemical Society
2024
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| Online Access: | https://hdl.handle.net/1721.1/156899 |
| _version_ | 1824458245221122048 |
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| author | Shi, Dennis Toyonaga, Sho Anderson, Daniel G |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering Shi, Dennis Toyonaga, Sho Anderson, Daniel G |
| author_sort | Shi, Dennis |
| collection | MIT |
| description | Ex vivo autologous hematopoietic stem cell (HSC) gene therapy has provided new therapies for the treatment of hematological disorders. However, these therapies have several limitations owing to the manufacturing complexities and toxicity resulting from required conditioning regimens. Here, we developed a c-kit (CD117) antibody-targeted lipid nanoparticle (LNP) that, following a single intravenous injection, can deliver RNA (both siRNA and mRNA) to HSCs in vivo in rodents. This targeted delivery system does not require stem cell harvest, culture, or mobilization of HSCs to facilitate delivery. We also show that delivery of Cre recombinase mRNA at a dose of 1 mg kg-1 can facilitate gene editing to almost all (∼90%) hematopoietic stem and progenitor cells (HSPCs) in vivo, and edited cells retain their stemness and functionality to generate high levels of edited mature immune cells. |
| first_indexed | 2024-09-23T13:30:14Z |
| format | Article |
| id | mit-1721.1/156899 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2025-02-19T04:22:49Z |
| publishDate | 2024 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | mit-1721.1/1568992025-01-04T04:39:16Z In Vivo RNA Delivery to Hematopoietic Stem and Progenitor Cells via Targeted Lipid Nanoparticles Shi, Dennis Toyonaga, Sho Anderson, Daniel G Massachusetts Institute of Technology. Department of Chemical Engineering Koch Institute for Integrative Cancer Research at MIT Ex vivo autologous hematopoietic stem cell (HSC) gene therapy has provided new therapies for the treatment of hematological disorders. However, these therapies have several limitations owing to the manufacturing complexities and toxicity resulting from required conditioning regimens. Here, we developed a c-kit (CD117) antibody-targeted lipid nanoparticle (LNP) that, following a single intravenous injection, can deliver RNA (both siRNA and mRNA) to HSCs in vivo in rodents. This targeted delivery system does not require stem cell harvest, culture, or mobilization of HSCs to facilitate delivery. We also show that delivery of Cre recombinase mRNA at a dose of 1 mg kg-1 can facilitate gene editing to almost all (∼90%) hematopoietic stem and progenitor cells (HSPCs) in vivo, and edited cells retain their stemness and functionality to generate high levels of edited mature immune cells. 2024-09-18T20:48:46Z 2024-09-18T20:48:46Z 2023-04-12 2024-09-18T20:41:30Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/156899 Dennis Shi, Sho Toyonaga, and Daniel G. Anderson Nano Letters 2023 23 (7), 2938-2944. en 10.1021/acs.nanolett.3c00304 Nano Letters Creative Commons Attribution https://creativecommons.org/licenses/by/4.0/ application/pdf American Chemical Society American Chemical Society |
| spellingShingle | Shi, Dennis Toyonaga, Sho Anderson, Daniel G In Vivo RNA Delivery to Hematopoietic Stem and Progenitor Cells via Targeted Lipid Nanoparticles |
| title | In Vivo RNA Delivery to Hematopoietic Stem and Progenitor Cells via Targeted Lipid Nanoparticles |
| title_full | In Vivo RNA Delivery to Hematopoietic Stem and Progenitor Cells via Targeted Lipid Nanoparticles |
| title_fullStr | In Vivo RNA Delivery to Hematopoietic Stem and Progenitor Cells via Targeted Lipid Nanoparticles |
| title_full_unstemmed | In Vivo RNA Delivery to Hematopoietic Stem and Progenitor Cells via Targeted Lipid Nanoparticles |
| title_short | In Vivo RNA Delivery to Hematopoietic Stem and Progenitor Cells via Targeted Lipid Nanoparticles |
| title_sort | in vivo rna delivery to hematopoietic stem and progenitor cells via targeted lipid nanoparticles |
| url | https://hdl.handle.net/1721.1/156899 |
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