Lipid Nanoparticle Assisted mRNA Delivery for Potent Cancer Immunotherapy
Open accessAbstract
The induction of a strong cytotoxic T cell response is an important prerequisite for successful immunotherapy against many viral diseases and tumors. Nucleotide vaccines, including mRNA vaccines with their intracellular antigen synthesis, have been shown to be potent activators of a cytotoxic immune response. The intracellular delivery of mRNA vaccines to the cytosol of antigen presenting immune cells is still not sufficiently well understood. Here, we report on the development of a lipid nanoparticle formulation for the delivery of mRNA vaccines to induce a cytotoxic CD 8 T cell response. We show transfection of dendritic cells, macrophages, and neutrophils. The efficacy of the vaccine was tested in an aggressive B16F10 melanoma model. We found a strong CD 8 T cell activation after a single immunization. Treatment of B16F10 melanoma tumors with lipid nanoparticles containing mRNA coding for the tumor-associated antigens gp100 and TRP2 resulted in tumor shrinkage and extended the overall survival of the treated mice. The immune response can be further increased by the incorporation of the adjuvant LPS. In conclusion, the lipid nanoparticle formulation presented here is a promising vector for mRNA vaccine delivery, one that is capable of inducing a strong cytotoxic T cell response. Further optimization, including the incorporation of different adjuvants, will likely enhance the potency of the vaccine.
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CD8+ T-cell responses induced by LNP-formulated mRNAs with unmodified nucleotides can exceed those induced by LNP-formulated mRNAs with modified nucleotides.
“They primarily induce CD8+ T-cell responses [22], which can exceed those induced by LNP-formulated mRNAs with modified nucleotides [34, 35], as well as CD4+ T-cell responses.”
From Preclinical development of an mRNA-based multiepitope immunotherapeutic for glioblastoma (2025) · cites this paper as [34]
LNP formulations optimized for siRNA delivery do not efficiently deliver large nucleic acids such as mRNAs and plasmids.
“However, LNP formulations that were optimized for small interfering RNA (siRNA) delivery do not efficiently deliver large nucleic acids (e.g., mRNAs and plasmids) (7, 8).”
From CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy (2020) · cites this paper as [8]
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“They primarily induce CD8 + T-cell responses [22], which can exceed those induced by LNP-formulated mRNAs with modified nucleotides [34, 35], as well as CD4 + T-cell responses.”
- Authors
- Oberli, M. A., Reichmuth, A. M., Dorkin, J. R., Mitchell, M. J., Fenton, O. S., Jaklenec, A., Anderson, D. G., Langer, R., & Blankschtein, D.
- Affiliations
- Harvard–MIT Division of Health Sciences and Technology (US)
- Boston Children's Hospital (US)
- Department of Anesthesiology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
- Corresponding author
- Blankschtein, Daniel
- ORCID
- Venue
- Nano Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-12-05
- Volume
- 17
- Issue
- 3
- Pages
- 1326-1335
- ISSN
- 1530-6984 (ISSN-L)
- 1530-6992
- PMC
- PMC5523404
- OpenAlex
- W2554094503
- Cited by
- 719
- References
- 54
- Citations by year
- 2026: 63 · 2025: 74 · 2024: 93 · 2023: 116 · 2022: 101 · 2021: 76 · 2020: 61 · 2019: 66 · 2018: 44 · 2017: 25
- FWCI
- 23.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nano Letters (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Cancer Institute (F32CA200351)
- Max-Planck-Gesellschaft
- Burroughs Wellcome Fund (1015145)
- Ragon Institute of MGH, MIT and Harvard
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- lipid nanoparticles, mRNA vaccines, cancer immunotherapy, cytotoxic T lymphocyte response, dendritic cells, macrophages, neutrophils, B16F10 melanoma, gp100, TRP-2, tumor-associated antigens, nucleic acid delivery
- MeSH terms
- Animals, Cytotoxicity, Immunologic, Humans, Immunotherapy, Lipids, Melanoma, Experimental, Mice, Inbred C57BL, Ovalbumin, RNA, Messenger, Vaccines, Synthetic, CD8-Positive T-Lymphocytes, Cancer Vaccines, Nanoparticles
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