Cell reports. Medicine · 2025
Modulation of lipid nanoparticle-formulated plasmid DNA drives innate immune activation promoting adaptive immunity.
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Tursi Nicholas J, Tiwari Sachchidanand, Bedanova Nicole, Kannan Toshitha, Parzych Elizabeth, Okba Nisreen, Liaw Kevin, Sárközy András, Livingston Cory, Trullen Maria Ibanez, Gary Ebony N, Vadovics Máté, Laenger Niklas, Londregan Jennifer, Khan Mohammad Suhail, Omo-Lamai Serena, Muramatsu Hiromi, Blatney Kerry, Hojecki Casey, Machado Viviane, Maricic Igor, Smith Trevor R F, Humeau Laurent M, Patel Ami, Kossenkov Andrew, Brenner Jacob S, Allman David, Krammer Florian, Pardi Norbert, Weiner David B
Аннотация
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+ 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.