Carl R. Woese Institute for Genomic Biology

Researchers in Professor of Bioengineering Xing Wang’s (CGD) lab discovered the influential role of structural chirality, or “handedness”, of a DNA nanostructure in dictating cancer cell response to targeted therapeutics. The study published in Advanced Materials reported that “left-handed” chiral configurations of aptamers—arranged on a DNA origami tube and targeting the cell surface protein CD117—were internalized by the acute myeloid leukemia cells much more efficiently than nanostructures with the “right-handed” patterns. 

“This ‘cellular enantioselectivity’ enables the left-handed delivery vehicle to deliver an anti-cancer drug with more than double the cancer-killing efficacy compared to its right-handed counterpart,” reported Wang. 

Chirality is a property that refers to the directionality or “handedness” of a structure. For example, the left and right hand on the human body are the same in form but are mirror images. While they can be lined up opposite to each other, the hands are non-superimposable. Similar in structure, gloves can be chiral or achiral—lacking directionality. Cheap pairs of plastic or fabric gloves, for example, are designed to be able to be worn on either hand; with an extra plane of symmetry, these are considered achiral.

For many chemicals, this same principle applies. Two molecules can be made of the same atoms, connected in the same way, but have entirely different properties if they are chiral. One familiar example is the artificial sweetener aspartame. One form of aspartame is able to bind to the sweetness taste receptors on the tongue. But when aspartame has a different chirality, it can no longer fit into the same receptor, instead resulting in a bitter taste. 

In essence, chirality is describing how molecular structures take up three-dimensional spaces. What makes Wang’s research interesting is that his team was able to generate structural chirality in tube-shaped DNA nanostructures. 

“Traditionally, researchers focused primarily on the chemical sequence of molecular binder,” said Tingjie Song, a postdoctoral researcher in Wang’s group and co-first author of the study. “But our work shows that the geometric pattern is also critical for biological function. This discovery opens doors to a new generation of ‘chiral switches’ and delivery vehicles that can be fine-tuned to match the specific 3D architecture of cell surface proteins.”

To build their chiral nanostructures, Song first started by designing a tubed-shaped DNA scaffold. At this point, the DNA tube is achiral. The aptamers were then attached to docking sites located on the tube, which come in the form of exposed DNA sequences that are complementary to part of the aptamers’ DNA code. Song strategically positioned these sites on the nanostructure’s surface to creating a spiral pattern of aptamers. 

To visualize this, the chiral nanostructures can be compared to nails and screws found in a toolbox. Before attaching the aptamers, the DNA tube is like a nail: achiral because it is smooth and symmetrical around its axis. While the left- and right-handed versions are the same structure, their patterned-aptamers spiral in opposite directions around the DNA tube, loosely resembling screws. Due to the direction of their helical threading, most screws are turned clockwise, or to the right, to tighten. But some situations, like securing the left pedal of a bike from falling off, require the less common left-handed screw, which instead must be driven counterclockwise due to its opposite chirality.

Wang’s team found that the left-handed construct was preferred when they tested the biological activity of their chiral nanostructures on acute myeloid leukemia cells. “After two hours of incubation, we found out that for the left-handed structures, there is a higher signal from the cells,” said Abhisek Dwivedy, co-first author of the paper. “This was interesting to us because other than the handedness, the structures were exactly the same.”

Upon further investigation, and contrary to the team’s expectations, while left- and right-handed nanostructures attached to the cell surface at nearly identical rates initially, the cells later “accepted” and pulled in the left-handed tubes. The right-handed structures were eventually rejected and detached.

Verifying their approach to ensure accurate drug-delivery release, in contrast to traditional delivery methods, the team studied Daunorubicin, a well-known chemotherapy drug.

“Traditional Daunorubicin therapy lacks targeting specificity, leading to significant off-target toxicity such as hepatic or renal toxicities and heart damage. By attaching daunorubicin to our chiral DNA-aptamer tubes, the drug is delivered specifically to cancer cells expressing the CD117 biomarker,” Dwivedy said.

The team found that the left-handed design promoted CD117 dimerization and triggered efficient cellular uptake. Upon tube entry into the cancer cell, the drug is released directly into the cell’s interior to cause DNA damage and cell death. This approach ensures the drug is released only where needed.

This study is part of the Wang lab’s overarching goal to remedy the critical challenges posed by cancer chemotherapy’s off-target toxicities. Further, their strategy is modular, and both DNA nanostructures and aptamers are relatively easy to design and customize, providing an avenue to expand this technology for many types of cancers.

“Our lab seeks to solve this problem by developing ‘smart’ DNA nanostructure-based delivery vehicles that recognize and enter cancer cells, such as acute myeloid leukemia cells. By combining DNA nanotechnology and aptamer engineering, we aim to increase drug efficacy while significantly reducing off target toxicities,” Wang said.

With the ultimate goal of clinical translation and practical cancer treatment, the team’s chiral DNA-based drug delivery system will need to undergo further laboratory testing to study immune system reactions and ensure the nanostructures are not cleared prematurely.

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Xing Wang is Associate Professor in the Department of Bioengineering at the University of Illinois Urbana-Champaign. Wang is also an affiliate of the Department of Chemistry, the Micro and Nanotechnology Lab, and the Cancer Center at Illinois.

The paper “DNA Origami-Templated Aptamer Chiral Structures Realize Cellular Enantioselectivity” is published in Advanced Materials and is available here.

DOI: doi.org/10.1002/adma.202519007