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

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

TLDR

  • The study found that spacing CpG oligonucleotides at a certain distance can help activate dendritic cells, which are important for the immune system. The study used a square-block DNA origami platform to test this idea. The results showed that spacing CpG at 3.5 nm induced Th1 immune polarization and enhanced DC activation, antigen cross-presentation, CD8 T-cell activation, Th1-polarized CD4 activation, and natural-killer-cell activation. The study also found that the vaccine effectively synergized with anti-PD-L1 for improved cancer immunotherapy in melanoma and lymphoma models and induced long-term T-cell memory. This means that DNA origami may be a useful tool for creating vaccines that work better and last longer.

Abstract

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.

Overview

  • The study explores the importance of spacing of CpG oligonucleotides in activating dendritic cells (DCs) through a square-block DNA origami platform. The hypothesis being tested is that spacing of CpG at 3.5 nm will induce Th1 immune polarization and enhance DC activation, antigen cross-presentation, CD8 T-cell activation, Th1-polarized CD4 activation, and natural-killer-cell activation. The methodology used includes in vitro cell culture studies and in vivo tumor treatment models. The primary objective of the study is to demonstrate the potential of DNA origami as a platform for controlling adjuvant spacing and co-delivering antigens in vaccines.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions, specifically the spacing of CpG oligonucleotides. The results show that spacing CpG at 3.5 nm induces Th1 immune polarization and enhances DC activation, antigen cross-presentation, CD8 T-cell activation, Th1-polarized CD4 activation, and natural-killer-cell activation. The study also demonstrates that the vaccine effectively synergizes with anti-PD-L1 for improved cancer immunotherapy in melanoma and lymphoma models and induces long-term T-cell memory. The key findings of the study support the hypothesis that DNA origami may serve as a platform for controlling adjuvant spacing and co-delivering antigens in vaccines.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they suggest that DNA origami may serve as a platform for controlling adjuvant spacing and co-delivering antigens in vaccines. The study identifies limitations, such as the need for further research to optimize the spacing of CpG oligonucleotides and to explore the use of DNA origami in other types of vaccines. Possible future research directions include optimizing the spacing of CpG oligonucleotides, exploring the use of DNA origami in other types of vaccines, and investigating the long-term efficacy and safety of DNA origami vaccines.
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