Discrete Immolative Guanidinium Transporters deliver mRNA to specific organs and red blood cells
Abstract RNA medicine is an emerging groundbreaking technology for the prevention and treatment of disease. However, tools to deliver messenger RNA (mRNA) and other polyanions (circRNA, saRNA, pDNA, CRISPR-Cas, reprogramming factors) are required to advance current RNA therapies and address next gen...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62200-3 |
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| author | Zhijian Li Aloysius Ee Laura Amaya Jennifer L. Hamad Pavan K. Yadav Sean K. Wang Howard Y. Chang Paul A. Wender |
| author_facet | Zhijian Li Aloysius Ee Laura Amaya Jennifer L. Hamad Pavan K. Yadav Sean K. Wang Howard Y. Chang Paul A. Wender |
| author_sort | Zhijian Li |
| collection | DOAJ |
| description | Abstract RNA medicine is an emerging groundbreaking technology for the prevention and treatment of disease. However, tools to deliver messenger RNA (mRNA) and other polyanions (circRNA, saRNA, pDNA, CRISPR-Cas, reprogramming factors) are required to advance current RNA therapies and address next generation challenges. Existing delivery systems often suffer from laborious syntheses, limited organ selectivity, formulation complexity, and undesired inflammatory responses. Here, we report novel mRNA delivery systems termed Discrete Immolative Guanidinium Transporters (DIGITs), which are synthesized convergently in as few as 4 steps. Unlike most cationic (ammonium) delivery systems, DIGITs are based on cationic guanidinium moieties, which complex mRNA at acidic pH and undergo irreversible neutralization at physiological pH to enable efficient RNA release. Systematic evaluation of structural variations and formulations have led to DIGIT/mRNA complexes that selectively target lung, spleen, and immature red blood cells in peripheral blood in female mice model. DIGIT/mRNA delivery systems show minimal toxicity based on cell viability and biochemical assays, supporting their future utility in biomedical applications. |
| format | Article |
| id | doaj-art-99bc7a190fd64391bdf14cdab769e584 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-99bc7a190fd64391bdf14cdab769e5842025-08-20T04:03:06ZengNature PortfolioNature Communications2041-17232025-08-0116111210.1038/s41467-025-62200-3Discrete Immolative Guanidinium Transporters deliver mRNA to specific organs and red blood cellsZhijian Li0Aloysius Ee1Laura Amaya2Jennifer L. Hamad3Pavan K. Yadav4Sean K. Wang5Howard Y. Chang6Paul A. Wender7Department of Chemistry, Stanford UniversityDepartment of Chemistry, Stanford UniversityCenter for Personal Dynamic Regulomes, Stanford UniversityDepartment of Chemistry, Stanford UniversityDepartment of Chemistry, Stanford UniversityCenter for Personal Dynamic Regulomes, Stanford UniversityCenter for Personal Dynamic Regulomes, Stanford UniversityDepartment of Chemistry, Stanford UniversityAbstract RNA medicine is an emerging groundbreaking technology for the prevention and treatment of disease. However, tools to deliver messenger RNA (mRNA) and other polyanions (circRNA, saRNA, pDNA, CRISPR-Cas, reprogramming factors) are required to advance current RNA therapies and address next generation challenges. Existing delivery systems often suffer from laborious syntheses, limited organ selectivity, formulation complexity, and undesired inflammatory responses. Here, we report novel mRNA delivery systems termed Discrete Immolative Guanidinium Transporters (DIGITs), which are synthesized convergently in as few as 4 steps. Unlike most cationic (ammonium) delivery systems, DIGITs are based on cationic guanidinium moieties, which complex mRNA at acidic pH and undergo irreversible neutralization at physiological pH to enable efficient RNA release. Systematic evaluation of structural variations and formulations have led to DIGIT/mRNA complexes that selectively target lung, spleen, and immature red blood cells in peripheral blood in female mice model. DIGIT/mRNA delivery systems show minimal toxicity based on cell viability and biochemical assays, supporting their future utility in biomedical applications.https://doi.org/10.1038/s41467-025-62200-3 |
| spellingShingle | Zhijian Li Aloysius Ee Laura Amaya Jennifer L. Hamad Pavan K. Yadav Sean K. Wang Howard Y. Chang Paul A. Wender Discrete Immolative Guanidinium Transporters deliver mRNA to specific organs and red blood cells Nature Communications |
| title | Discrete Immolative Guanidinium Transporters deliver mRNA to specific organs and red blood cells |
| title_full | Discrete Immolative Guanidinium Transporters deliver mRNA to specific organs and red blood cells |
| title_fullStr | Discrete Immolative Guanidinium Transporters deliver mRNA to specific organs and red blood cells |
| title_full_unstemmed | Discrete Immolative Guanidinium Transporters deliver mRNA to specific organs and red blood cells |
| title_short | Discrete Immolative Guanidinium Transporters deliver mRNA to specific organs and red blood cells |
| title_sort | discrete immolative guanidinium transporters deliver mrna to specific organs and red blood cells |
| url | https://doi.org/10.1038/s41467-025-62200-3 |
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