Modulation of lipid nanoparticle-formulated plasmid DNA drives innate immune activation promoting adaptive immunity
Nucleic acid vaccines have grown in importance over the past several years, with the development of new approaches remaining a focus. We describe a lipid nanoparticle-formulated DNA (DNA-LNP) formulation which induces robust innate and adaptive immunity with similar serological potency to mRNA-LNPs and adjuvanted protein. Using an influenza hemagglutinin (HA)-encoding construct, we show that priming with our HA DNA-LNP demonstrated stimulator of interferon genes (STING)-dependent upregulation and activation of migratory dendritic cell (DC) subpopulations. HA DNA-LNP induced superior antigen-specific CD8<sup>+</sup> T cell responses relative to mRNA-LNPs or adjuvanted protein, with memory responses persisting beyond one year. In rabbits immunized with HA DNA-LNP, we observed immune responses comparable or superior to mRNA-LNPs at the same dose. In an additional model, a SARS-CoV-2 spike-encoding DNA-LNP elicited protective efficacy comparable to spike mRNA-LNPs. Our study identifies a platform-specific priming mechanism for DNA-LNPs divergent from mRNA-LNPs or adjuvanted protein, suggesting avenues for this approach in prophylactic and therapeutic vaccine development.
Authors
- Nicholas J. Tursi (ORCID: https://orcid.org/0000-0001-6752-3402)
- Andrew V. Kossenkov (ORCID: https://orcid.org/0000-0002-1536-0418)
- Laurent Humeau
- Igor Maricic
- David B. Weiner (ORCID: https://orcid.org/0000-0002-2232-8512)
- M. S. A. Alam Khan (ORCID: https://orcid.org/0000-0003-2385-8504)
- E. Gary (ORCID: https://orcid.org/0000-0002-2928-1120)
- Jennifer Londregan (ORCID: https://orcid.org/0000-0003-2236-3577)
- Kevin Liaw (ORCID: https://orcid.org/0000-0002-8235-1407)
- Carissa E. Livingston (ORCID: https://orcid.org/0000-0003-0052-2784)
- Ami Patel (ORCID: https://orcid.org/0000-0002-2104-9984)
- Trevor R. F. Smith
- Casey E. Hojecki
- Sachchidanand Tiwari (ORCID: https://orcid.org/0000-0003-1541-5092)
- David Allman (ORCID: https://orcid.org/0000-0001-9345-1502)
- Norbert Pardi (ORCID: https://orcid.org/0000-0003-1008-6242)
- Nisreen M.A. Okba (ORCID: https://orcid.org/0000-0002-2394-1079)
- Florian Krammer (ORCID: https://orcid.org/0000-0003-4121-776X)
- Toshitha Kannan (ORCID: https://orcid.org/0009-0007-7775-6585)
- Elizabeth M. Parzych (ORCID: https://orcid.org/0000-0001-9342-3499)
- Hiromi Muramatsu (ORCID: https://orcid.org/0000-0003-1544-1493)
- Máté Vadovics (ORCID: https://orcid.org/0000-0001-9028-987X)
- Viviane M. Andrade (ORCID: https://orcid.org/0000-0002-5056-298X)
- Nicole M. Bedanova (ORCID: https://orcid.org/0000-0002-0962-9601)
- Niklas Laenger
- Serena Omo-Lamai
- András Sárközy
- Maria Ibanez Trullen
- Kerry Blatney
Institutions
- The Wistar Institute (US)
- Translational Therapeutics (United States) (US)
- Inovio Pharmaceuticals (United States) (US)
- Saint Joseph's University (US)
- University of Pennsylvania (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-03-22
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102035
- Citations
- 18
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 14.35
Funders
- W. W. Smith Charitable Trust
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- INOVIO Pharmaceuticals
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases