Journal Article

Fine tuning of CpG spatial distribution with DNA origami for improved cancer vaccination

Sobral, Miguel, Neuberg, Donna, Young, Olivia J., Choi, Youngjin, Keskin, Derin B., Mooney, David J., MacDonald, James I., Fell, Geoffrey G., Wu, Catherine J., Graveline, Amanda R., Vernet, Andyna, Isinelli, Giorgia, Dellacherie, Maxence O., Mulligan, Kathleen, Kwon, Ick Chan, Ryu, Ju Hee, Anastassacos, Frances M., Ferrante, Thomas C., Sanchez, Melinda, Zeng, Yang C., Bai, Haiqing, Wintersinger, Christopher M., Shih, William M.

2024

Overview

Multivalent presentation of ligands often enhances receptor activation and downstream signalling. DNA origami offers a precise nanoscale spacing of ligands, a potentially useful feature for therapeutic nanoparticles. Here we use a square-block DNA origami platform to explore the importance of the spacing of CpG oligonucleotides. CpG engages Toll-like receptors and therefore acts to activate dendritic cells. Through in vitro cell culture studies and in vivo tumour 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 natural-killer-cell activation. The vaccine also effectively synergizes 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 a platform for controlling adjuvant spacing and co-delivering antigens in vaccines. The spacing of ligands presented to cells can have a huge impact on cellular responses. DNA origami is used to block structures to control the distribution of Toll-like receptor ligands and optimize presentation in the activation of dendritic cells in cancer immunotherapy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/61/350/2093 / 631/61/54/152 / Animals / Antigen presentation / Antigens / Cancer / Cancer immunotherapy / Cancer vaccines / Cancer Vaccines - chemistry / Cancer Vaccines - immunology / CD4 antigen / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Cell activation / Cell culture / Cell Line, Tumor / Cellular structure / Chemistry and Materials Science / CpG Islands / Dendritic cells / Dendritic Cells - immunology / Deoxyribonucleic acid / DNA / DNA - chemistry / DNA - immunology / DNA vaccines / Female / Humans / Immune system / Immunological memory / Immunotherapy / In vivo methods and tests / Ligands / Lymphocytes T / Lymphoma / Materials Science / Mathematical models / Melanoma / Mice / Mice, Inbred C57BL / Nanoparticles / Nanotechnology / Nanotechnology and Microengineering / Oligodeoxyribonucleotides - chemistry / Oligodeoxyribonucleotides - pharmacology / Oligonucleotides / PD-L1 protein / Proteins / Receptor mechanisms / Spatial distribution / Toll-like receptors / Vaccination - methods / Vaccines / Vaccines, DNA - chemistry / Vaccines, DNA - immunology / Vaccines, DNA - pharmacology