Optimizing CpG spatial distribution with DNA origami for Th1-polarized therapeutic vaccination

Zeng, Y. C.; Young, O. J.; Wintersinger, C. M.; Anastassacos, F. M.; MacDonald, J. I.; Isinelli, G.; Dellacherie, M. O.; Sobral, M.; Bai, H.; Graveline, A.; Vernet, A.; Sanchez-Ventura, M.; Mulligan, K.; Choi, Y.-J.; Ferrante, T. C.; Keskin, D.; Wu, C.; Mooney, D.; Kwon, I.-C.; Ryu, J.-H.; Shih, W.

doi:10.1101/2022.06.08.495340

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bioRxiv · 10.1101/2022.06.08.495340

Optimizing CpG spatial distribution with DNA origami for Th1-polarized therapeutic vaccination

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Abstract

Multivalent presentation of ligands often enhances receptor activation and downstream signaling. DNA origami offers precise nanoscale spacing of ligands, a potentially useful feature for therapeutic nanoparticles. Here we introduce a "square block" DNA origami platform to explore the importance of spacing of CpG oligonucleotides, which engage Toll-like receptors and thereby act as danger signals for dendritic cells. Through in vitro cell-culture studies and in vivo tumor-treatment models, we demonstrate that square blocks induce Th1 immune polarization when CpG is spaced at 3.5 nm. We observe that this DNA origami vaccine enhances DC activation, antigen cross-presentation, CD8 T cell activation, Th1-polarized CD4 activation and NK cell activation. The vaccine also synergizes effectively with anti-PD-L1 for improved cancer immunotherapy in melanoma and lymphoma models and induces long-term T cell memory. Our results suggest that DNA origami may serve as an advanced vaccine platform for controlling adjuvant spacing and co-delivering antigens. One Sentence SummaryThis study developed a DNA origami-based cancer vaccine (DoriVac) that co-delivers antigen and CpG immune adjuvant with an optimal nanospacing for Th1 immune polarization.

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Zeng, Y. C., Young, O. J., Wintersinger, C. M., Anastassacos, F. M., MacDonald, J. I., Isinelli, G., Dellacherie, M. O., Sobral, M., Bai, H., Graveline, A., Vernet, A., Sanchez-Ventura, M., Mulligan, K., Choi, Y.-J., Ferrante, T. C., Keskin, D., Wu, C., Mooney, D., Kwon, I.-C., Ryu, J.-H., Shih, W.. 2022-06-08. Optimizing CpG spatial distribution with DNA origami for Th1-polarized therapeutic vaccination. https://doi.org/10.1101/2022.06.08.495340

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