Engineering DNA Nanostructures to Manipulate Immune Receptor Signaling and Immune Cell Fates

Abstract

Immune cells sense, communicate, and logically integrate a multitude of environmental signals to make important cell-fate decisions and fulfill their effector functions. These processes are initiated and regulated by a diverse array of immune receptors and via their dynamic spatiotemporal organization upon ligand binding. Given the widespread relevance of the immune system to health and disease, there have been significant efforts toward understanding the biophysical principles governing immune receptor signaling and activation, as well as the development of biomaterials which exploit these principles for therapeutic immune engineering. Here, how advances in the field of DNA nanotechnology constitute a growing toolbox for further pursuit of these endeavors is discussed. Key cellular players involved in the induction of immunity against pathogens or diseased cells are first summarized. How the ability to design DNA nanostructures with custom shapes, dynamics, and with site-specific incorporation of diverse guests can be leveraged to manipulate the signaling pathways that regulate these processes is then presented. It is followed by highlighting emerging applications of DNA nanotechnology at the crossroads of immune engineering, such as in vitro reconstitution platforms, vaccines, and adjuvant delivery systems. Finally, outstanding questions that remain for further advancing immune-modulatory DNA nanodevices are outlined.

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

“…Recent advances have illustrated the potential benefits of DNA origami in the context of cancer immunotherapy 19,20,48 . Several studies have demonstrated that the spatial arrangements of ligands on DNA origami resulted in significant differences in activation of their cognate receptors and downstream signaling in cells [49][50][51] .…”

origamiFISH allows universal, label-free, single molecule visualization of DNA origami nanodevices across biological samples

“…origamiFISH takes advantage of the presence of a long, circular scaffold DNA sequence that is present within DNA origami nanostructures ( Fig. 1a ) (Seeman and Sleiman, 2017; Tseng et al, 2022). In nearly all cases, DN scaffolds are derived from the 7249-nt genome of M13mp18 bacteriophage, with variants containing either sequence insertions (e.g.…”

“…It has previously been shown that the vast majority of nanoparticles localize to Lamp1+ lysosomes as their final destination within cells (Shapero et al, 2011). Consequently, targeting of endo-lysosomal receptors is emerging as an important strategy in nanoparticle-based therapeutics (Comberlato et al, 2022; Tseng et al, 2022). To visualize if DNs similarly traffic to lysosomal compartments, we co-stained origamiFISH with Lamp1 antibodies following 30 minute uptake of DN rectangles in RAW264.7 cells.…”

“…DNA origami nanostructures (DNs) enable rapid prototyping of highly monodisperse and user-prescribed nanoscale devices (Dey et al, 2021; Hong et al, 2017; Rothemund, 2006; Tseng et al, 2022). Combining compatibility for macromolecule decorations (i.e.…”

Direct visualization of the drug loading of single DNA origami nanostructures by AFM-IR nanospectroscopy

“…[3][4][5] However, DNA nanocarriers are also increasingly explored with regard to applications in immunotherapy and in the treatment and prevention of infectious diseases. [6][7][8] While numerous different therapeutic species can be transported by such nanostructures, including enzymes, 9 therapeutic nucleic acids, 10 and nanoparticles, 11 DNA-based nanocarriers are mostly employed in the delivery of chemotherapeutic drug molecules. 1,2 This is mainly because many of such chemotherapeutic drugs have a high affinity for DNA and can thus be easily loaded into the DNA nanostructures.…”