CD47 Knock‐Out Using CRISPR‐Cas9 RNA Lipid Nanocarriers Results in Reduced Mesenchymal Glioblastoma Growth In Vivo
Abstract Immune checkpoint (ICP) blockade has shown limited effectiveness in glioblastoma (GBM), particularly in the mesenchymal subtype, where interactions between immune cells and glioblastoma cancer stem cells (GSCs) drive immunosuppression and therapy resistance. Tailoring ICPs specific to GSCs...
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| Format: | Article |
| Language: | English |
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Wiley
2025-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202407262 |
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| author | Nadia Rouatbi Adam A. Walters Alaa Zam Yau Mun Lim Alessia Marrocu Revadee Liam‐Or Joanne E. Anstee James N. Arnold Julie Tzu‐Wen Wang Steven M. Pollard Khuloud T. Al‐Jamal |
| author_facet | Nadia Rouatbi Adam A. Walters Alaa Zam Yau Mun Lim Alessia Marrocu Revadee Liam‐Or Joanne E. Anstee James N. Arnold Julie Tzu‐Wen Wang Steven M. Pollard Khuloud T. Al‐Jamal |
| author_sort | Nadia Rouatbi |
| collection | DOAJ |
| description | Abstract Immune checkpoint (ICP) blockade has shown limited effectiveness in glioblastoma (GBM), particularly in the mesenchymal subtype, where interactions between immune cells and glioblastoma cancer stem cells (GSCs) drive immunosuppression and therapy resistance. Tailoring ICPs specific to GSCs can enhance the antitumor immune response. This study proposes the use of lipid nanoparticles (LNPs) encapsulating CRISPR RNAs as an in vivo screening tool for ICPs in a syngeneic model of mesenchymal GSCs. Using PD‐L1 and CD47 to validate the proof of concept, intratumoral administration of LNPs in orthotopic tumors achieved efficient editing of ICPs, leading to enhanced immune cell infiltration within the tumor microenvironment. Targeting CD47 reduced tumor growth, suggesting improved cancer cell sensitization to the immune system post‐ICP editing. The study positions LNPs as a robust tool for in vivo validation of ICPs as therapeutic targets in clinically relevant GBM models. LNPs could serve as a screening tool in patient‐derived xenografts to identify and optimize ICP combinations, potentially expediting ICP translation and enhancing personalized GBM immunotherapies. |
| format | Article |
| id | doaj-art-a68ea34b6ae347aba53e7fb6c6ecf723 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-a68ea34b6ae347aba53e7fb6c6ecf7232025-08-20T01:49:41ZengWileyAdvanced Science2198-38442025-03-011212n/an/a10.1002/advs.202407262CD47 Knock‐Out Using CRISPR‐Cas9 RNA Lipid Nanocarriers Results in Reduced Mesenchymal Glioblastoma Growth In VivoNadia Rouatbi0Adam A. Walters1Alaa Zam2Yau Mun Lim3Alessia Marrocu4Revadee Liam‐Or5Joanne E. Anstee6James N. Arnold7Julie Tzu‐Wen Wang8Steven M. Pollard9Khuloud T. Al‐Jamal10Institute of Pharmaceutical Science Faculty of Life Sciences and Medicine King's College London Franklin‐Wilkins Building, 150 Stamford Street London SE1 9NH UKInstitute of Pharmaceutical Science Faculty of Life Sciences and Medicine King's College London Franklin‐Wilkins Building, 150 Stamford Street London SE1 9NH UKInstitute of Pharmaceutical Science Faculty of Life Sciences and Medicine King's College London Franklin‐Wilkins Building, 150 Stamford Street London SE1 9NH UKInstitute of Pharmaceutical Science Faculty of Life Sciences and Medicine King's College London Franklin‐Wilkins Building, 150 Stamford Street London SE1 9NH UKInstitute of Pharmaceutical Science Faculty of Life Sciences and Medicine King's College London Franklin‐Wilkins Building, 150 Stamford Street London SE1 9NH UKInstitute of Pharmaceutical Science Faculty of Life Sciences and Medicine King's College London Franklin‐Wilkins Building, 150 Stamford Street London SE1 9NH UKComprehensive Cancer Centre Faculty of Life Sciences and Medicine King's College London, Guy's Hospital London SE1 1UL UKComprehensive Cancer Centre Faculty of Life Sciences and Medicine King's College London, Guy's Hospital London SE1 1UL UKInstitute of Pharmaceutical Science Faculty of Life Sciences and Medicine King's College London Franklin‐Wilkins Building, 150 Stamford Street London SE1 9NH UKCentre for Regenerative Medicine Institute for Regeneration and Repair & Cancer Research UK Scotland Centre University of Edinburgh 5 Little France Drive Edinburgh EH16 4UU UKInstitute of Pharmaceutical Science Faculty of Life Sciences and Medicine King's College London Franklin‐Wilkins Building, 150 Stamford Street London SE1 9NH UKAbstract Immune checkpoint (ICP) blockade has shown limited effectiveness in glioblastoma (GBM), particularly in the mesenchymal subtype, where interactions between immune cells and glioblastoma cancer stem cells (GSCs) drive immunosuppression and therapy resistance. Tailoring ICPs specific to GSCs can enhance the antitumor immune response. This study proposes the use of lipid nanoparticles (LNPs) encapsulating CRISPR RNAs as an in vivo screening tool for ICPs in a syngeneic model of mesenchymal GSCs. Using PD‐L1 and CD47 to validate the proof of concept, intratumoral administration of LNPs in orthotopic tumors achieved efficient editing of ICPs, leading to enhanced immune cell infiltration within the tumor microenvironment. Targeting CD47 reduced tumor growth, suggesting improved cancer cell sensitization to the immune system post‐ICP editing. The study positions LNPs as a robust tool for in vivo validation of ICPs as therapeutic targets in clinically relevant GBM models. LNPs could serve as a screening tool in patient‐derived xenografts to identify and optimize ICP combinations, potentially expediting ICP translation and enhancing personalized GBM immunotherapies.https://doi.org/10.1002/advs.202407262CD47glioblastomaimmune checkpointimmunotherapynanoparticlesnucleic acid delivery |
| spellingShingle | Nadia Rouatbi Adam A. Walters Alaa Zam Yau Mun Lim Alessia Marrocu Revadee Liam‐Or Joanne E. Anstee James N. Arnold Julie Tzu‐Wen Wang Steven M. Pollard Khuloud T. Al‐Jamal CD47 Knock‐Out Using CRISPR‐Cas9 RNA Lipid Nanocarriers Results in Reduced Mesenchymal Glioblastoma Growth In Vivo Advanced Science CD47 glioblastoma immune checkpoint immunotherapy nanoparticles nucleic acid delivery |
| title | CD47 Knock‐Out Using CRISPR‐Cas9 RNA Lipid Nanocarriers Results in Reduced Mesenchymal Glioblastoma Growth In Vivo |
| title_full | CD47 Knock‐Out Using CRISPR‐Cas9 RNA Lipid Nanocarriers Results in Reduced Mesenchymal Glioblastoma Growth In Vivo |
| title_fullStr | CD47 Knock‐Out Using CRISPR‐Cas9 RNA Lipid Nanocarriers Results in Reduced Mesenchymal Glioblastoma Growth In Vivo |
| title_full_unstemmed | CD47 Knock‐Out Using CRISPR‐Cas9 RNA Lipid Nanocarriers Results in Reduced Mesenchymal Glioblastoma Growth In Vivo |
| title_short | CD47 Knock‐Out Using CRISPR‐Cas9 RNA Lipid Nanocarriers Results in Reduced Mesenchymal Glioblastoma Growth In Vivo |
| title_sort | cd47 knock out using crispr cas9 rna lipid nanocarriers results in reduced mesenchymal glioblastoma growth in vivo |
| topic | CD47 glioblastoma immune checkpoint immunotherapy nanoparticles nucleic acid delivery |
| url | https://doi.org/10.1002/advs.202407262 |
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