Lipid nanoparticles deliver DNA-encoded biologics and induce potent protective immunity
Abstract Lipid nanoparticles (LNPs) for mRNA delivery have advanced significantly, but LNP-mediated DNA delivery still faces clinical challenges. This study compared various LNP formulations for delivering DNA-encoded biologics, assessing their expression efficacy and the protective immunity generat...
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| Format: | Article |
| Language: | English |
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BMC
2025-01-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-024-02211-8 |
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| author | Dafei Chai Junhao Wang Jing Ming Lim Xiaohui Xie Xinfang Yu Dan Zhao Perry Ayn Mayson Maza Yifei Wang Dana Cyril-Remirez Ken H. Young Yong Li |
| author_facet | Dafei Chai Junhao Wang Jing Ming Lim Xiaohui Xie Xinfang Yu Dan Zhao Perry Ayn Mayson Maza Yifei Wang Dana Cyril-Remirez Ken H. Young Yong Li |
| author_sort | Dafei Chai |
| collection | DOAJ |
| description | Abstract Lipid nanoparticles (LNPs) for mRNA delivery have advanced significantly, but LNP-mediated DNA delivery still faces clinical challenges. This study compared various LNP formulations for delivering DNA-encoded biologics, assessing their expression efficacy and the protective immunity generated by LNP-encapsulated DNA in different models. The LNP formulation used in Moderna’s Spikevax mRNA vaccine (LNP-M) demonstrated a stable nanoparticle structure, high expression efficiency, and low toxicity. Notably, a DNA vaccine encoding the spike protein, delivered via LNP-M, induced stronger antigen-specific antibody and T cell immune responses compared to electroporation. Single-cell RNA sequencing (scRNA-seq) analysis revealed that the LNP-M/pSpike vaccine enhanced CD80 activation signaling in CD8+ T cells, NK cells, macrophages, and DCs, while reducing the immunosuppressive signals. The enrichment of TCR and BCR by LNP-M/pSpike suggested an increase in immune response specificity and diversity. Additionally, LNP-M effectively delivered DNA-encoded antigens, such as mouse PD-L1 and p53R172H, or monoclonal antibodies targeting mouse PD1 and human p53R282W. This approach inhibited tumor growth or metastasis in several mouse models. The long-term anti-tumor effects of LNP-M-delivered anti-p53R282W antibody relied on memory CD8+ T cell responses and enhanced MHC-I signaling from APCs to CD8+ T cells. These results highlight LNP-M as a promising and effective platform for delivering DNA-based vaccines and cancer immunotherapies. |
| format | Article |
| id | doaj-art-2f4fa4a437e448bca43204e07eadbc22 |
| institution | Kabale University |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-2f4fa4a437e448bca43204e07eadbc222025-01-19T12:12:41ZengBMCMolecular Cancer1476-45982025-01-0124112110.1186/s12943-024-02211-8Lipid nanoparticles deliver DNA-encoded biologics and induce potent protective immunityDafei Chai0Junhao Wang1Jing Ming Lim2Xiaohui Xie3Xinfang Yu4Dan Zhao5Perry Ayn Mayson Maza6Yifei Wang7Dana Cyril-Remirez8Ken H. Young9Yong Li10Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of MedicineDepartment of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of MedicineDepartment of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of MedicineDepartment of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of MedicineDepartment of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of MedicineDepartment of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of MedicineDepartment of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of MedicineDepartment of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of MedicineDepartment of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of MedicineDepartment of Pathology, Division of Hematopathology, Duke University Medical CenterDepartment of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of MedicineAbstract Lipid nanoparticles (LNPs) for mRNA delivery have advanced significantly, but LNP-mediated DNA delivery still faces clinical challenges. This study compared various LNP formulations for delivering DNA-encoded biologics, assessing their expression efficacy and the protective immunity generated by LNP-encapsulated DNA in different models. The LNP formulation used in Moderna’s Spikevax mRNA vaccine (LNP-M) demonstrated a stable nanoparticle structure, high expression efficiency, and low toxicity. Notably, a DNA vaccine encoding the spike protein, delivered via LNP-M, induced stronger antigen-specific antibody and T cell immune responses compared to electroporation. Single-cell RNA sequencing (scRNA-seq) analysis revealed that the LNP-M/pSpike vaccine enhanced CD80 activation signaling in CD8+ T cells, NK cells, macrophages, and DCs, while reducing the immunosuppressive signals. The enrichment of TCR and BCR by LNP-M/pSpike suggested an increase in immune response specificity and diversity. Additionally, LNP-M effectively delivered DNA-encoded antigens, such as mouse PD-L1 and p53R172H, or monoclonal antibodies targeting mouse PD1 and human p53R282W. This approach inhibited tumor growth or metastasis in several mouse models. The long-term anti-tumor effects of LNP-M-delivered anti-p53R282W antibody relied on memory CD8+ T cell responses and enhanced MHC-I signaling from APCs to CD8+ T cells. These results highlight LNP-M as a promising and effective platform for delivering DNA-based vaccines and cancer immunotherapies.https://doi.org/10.1186/s12943-024-02211-8Lipid nanoparticlesDNA-encoded biologicsVaccinesMonoclonal antibodiesCancer immunotherapy |
| spellingShingle | Dafei Chai Junhao Wang Jing Ming Lim Xiaohui Xie Xinfang Yu Dan Zhao Perry Ayn Mayson Maza Yifei Wang Dana Cyril-Remirez Ken H. Young Yong Li Lipid nanoparticles deliver DNA-encoded biologics and induce potent protective immunity Molecular Cancer Lipid nanoparticles DNA-encoded biologics Vaccines Monoclonal antibodies Cancer immunotherapy |
| title | Lipid nanoparticles deliver DNA-encoded biologics and induce potent protective immunity |
| title_full | Lipid nanoparticles deliver DNA-encoded biologics and induce potent protective immunity |
| title_fullStr | Lipid nanoparticles deliver DNA-encoded biologics and induce potent protective immunity |
| title_full_unstemmed | Lipid nanoparticles deliver DNA-encoded biologics and induce potent protective immunity |
| title_short | Lipid nanoparticles deliver DNA-encoded biologics and induce potent protective immunity |
| title_sort | lipid nanoparticles deliver dna encoded biologics and induce potent protective immunity |
| topic | Lipid nanoparticles DNA-encoded biologics Vaccines Monoclonal antibodies Cancer immunotherapy |
| url | https://doi.org/10.1186/s12943-024-02211-8 |
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