Ionizable lipid nanoparticles of mRNA vaccines elicit NF-κB and IRF responses through toll-like receptor 4
Abstract Ionizable lipid nanoparticles (LNP) that have enabled the success of messenger RNA (mRNA) vaccines have been shown to be immunostimulatory in the absence of mRNA. However, the mechanisms through which they activate innate immune cells is incompletely understood. Using a monocyte cell line,...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | npj Vaccines |
| Online Access: | https://doi.org/10.1038/s41541-025-01124-x |
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| author | Amanda E. Zelkoski Zhongyan Lu Gauthaman Sukumar Clifton Dalgard Hooda Said Mohamad-Gabriel Alameh Edward Mitre Allison M. W. Malloy |
| author_facet | Amanda E. Zelkoski Zhongyan Lu Gauthaman Sukumar Clifton Dalgard Hooda Said Mohamad-Gabriel Alameh Edward Mitre Allison M. W. Malloy |
| author_sort | Amanda E. Zelkoski |
| collection | DOAJ |
| description | Abstract Ionizable lipid nanoparticles (LNP) that have enabled the success of messenger RNA (mRNA) vaccines have been shown to be immunostimulatory in the absence of mRNA. However, the mechanisms through which they activate innate immune cells is incompletely understood. Using a monocyte cell line, we compared the ability of three LNP formulations to activate transcription factors Nuclear Factor-kappa B (NF-κB) and Interferon Regulatory Factor (IRF). Comparison of signaling in knockout cell lines illustrated a role for Toll-like receptor (TLR) 4 in initiation of this signaling cascade and the contribution of the ionizable lipid component. Activation induced by empty LNPs was similar to that induced by LNPs containing mRNA, indicating that LNPs may provide the majority of innate stimulation for the mRNA vaccine platform. Our findings demonstrate that ionizable lipids within LNPs signal through TLR4 to activate NF-κB and IRF, identifying a mechanism for innate activation that can be optimized for adjuvant design. |
| format | Article |
| id | doaj-art-e112d4deddbc4f26b0ee6e982f0bc5d3 |
| institution | DOAJ |
| issn | 2059-0105 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Vaccines |
| spelling | doaj-art-e112d4deddbc4f26b0ee6e982f0bc5d32025-08-20T03:18:53ZengNature Portfolionpj Vaccines2059-01052025-04-0110111310.1038/s41541-025-01124-xIonizable lipid nanoparticles of mRNA vaccines elicit NF-κB and IRF responses through toll-like receptor 4Amanda E. Zelkoski0Zhongyan Lu1Gauthaman Sukumar2Clifton Dalgard3Hooda Said4Mohamad-Gabriel Alameh5Edward Mitre6Allison M. W. Malloy7Department of Pediatrics, Uniformed Services University of Health SciencesDepartment of Pediatrics, Uniformed Services University of Health SciencesHenry M Jackson Foundation for the Advancement of Military MedicineDepartment of Anatomy, Physiology & Genetics, Uniformed Services University of Health SciencesDepartment of Pathology and Laboratory Medicine, Children’s Hospital of PhiladelphiaDepartment of Pathology and Laboratory Medicine, Children’s Hospital of PhiladelphiaDepartment of Microbiology and Immunology, Uniformed Services University of Health SciencesDepartment of Pediatrics, Uniformed Services University of Health SciencesAbstract Ionizable lipid nanoparticles (LNP) that have enabled the success of messenger RNA (mRNA) vaccines have been shown to be immunostimulatory in the absence of mRNA. However, the mechanisms through which they activate innate immune cells is incompletely understood. Using a monocyte cell line, we compared the ability of three LNP formulations to activate transcription factors Nuclear Factor-kappa B (NF-κB) and Interferon Regulatory Factor (IRF). Comparison of signaling in knockout cell lines illustrated a role for Toll-like receptor (TLR) 4 in initiation of this signaling cascade and the contribution of the ionizable lipid component. Activation induced by empty LNPs was similar to that induced by LNPs containing mRNA, indicating that LNPs may provide the majority of innate stimulation for the mRNA vaccine platform. Our findings demonstrate that ionizable lipids within LNPs signal through TLR4 to activate NF-κB and IRF, identifying a mechanism for innate activation that can be optimized for adjuvant design.https://doi.org/10.1038/s41541-025-01124-x |
| spellingShingle | Amanda E. Zelkoski Zhongyan Lu Gauthaman Sukumar Clifton Dalgard Hooda Said Mohamad-Gabriel Alameh Edward Mitre Allison M. W. Malloy Ionizable lipid nanoparticles of mRNA vaccines elicit NF-κB and IRF responses through toll-like receptor 4 npj Vaccines |
| title | Ionizable lipid nanoparticles of mRNA vaccines elicit NF-κB and IRF responses through toll-like receptor 4 |
| title_full | Ionizable lipid nanoparticles of mRNA vaccines elicit NF-κB and IRF responses through toll-like receptor 4 |
| title_fullStr | Ionizable lipid nanoparticles of mRNA vaccines elicit NF-κB and IRF responses through toll-like receptor 4 |
| title_full_unstemmed | Ionizable lipid nanoparticles of mRNA vaccines elicit NF-κB and IRF responses through toll-like receptor 4 |
| title_short | Ionizable lipid nanoparticles of mRNA vaccines elicit NF-κB and IRF responses through toll-like receptor 4 |
| title_sort | ionizable lipid nanoparticles of mrna vaccines elicit nf κb and irf responses through toll like receptor 4 |
| url | https://doi.org/10.1038/s41541-025-01124-x |
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