Study reveals structural chirality as a critical molecular design parameter for targeted cancer therapeutics

Researchers in the lab of Cancer Center at Illinois (CCIL) member Xing Wang discovered the influential role of structural chirality, or “handedness”, of a DNA nanostructure to dictate cancer cell response to targeted therapeutics. The team’s findings are reported in Advanced Materials.

The Wang lab found that “left-handed” chiral configurations of aptamers—arranged on a DNA origami tube targeting the cancer cell surface protein (CD117)—were internalized by cancer cells much more efficiently than “right-handed” patterns. Formation of the DNA tube and its ability to arrange external elements into left- or right-handed form was characterized by gel electrophoresis, transmission electron microscopy, and super-resolution fluorescence imaging (image was obtained through the collaboration with Prof. Yang Zhao).

“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, who was joined by researchers Tingjie Song and Abhisek Dwivedy on this research and the team’s publication.

To understand these research findings, it’s critical to understand the function of the same aptamer that is organized into different chiral structures enabled by a tubular-shaped designer DNA nanostructure as a scaffold. Chirality, or “handedness”, refers to the function of two objects that are mirror images of each other, but cannot perfectly overlap, like left and right hands on a human body. In the microscopic world of biology, most essential molecules like proteins and double stranded DNA are chiral. Cells respond differently to left- and right-handed molecules, including drugs, because their surface receptors are also “handed.” For example, ibuprofen, a common anti-inflammatory drug, is active only when present in its right-handed form. Like a glove, a left-handed glove only fits the left hand. If the drug-carrying “hand” doesn’t match the cell receptor’s “glove,” the cell won’t “grasp” it correctly.

The Wang lab’s discovery in this study introduces this nanoscale feature of structural chirality as a powerful new design parameter for targeted cancer therapeutics.

“Traditionally, researchers focused primarily on the chemical sequence of molecular binder,” said Song. “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.”

The discovery that left-handed designs internalized more than right-handed counterparts, despite being built from the exact same aptamer, is a keen and surprising observation, according to Wang. 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 and eventually rejected and detached the right-handed ones.

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,” said Dwivedy.

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. Many anti-cancer drugs harm healthy cells because they cannot be delivered precisely to tumors.

“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 (AML) cells. By combining DNA nanotechnology and aptamer engineering, we aim to increase drug efficacy while significantly reducing off target toxicities,” said Wang.

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.

Editor’s notes:

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 Carl R. Woese Institute for Genomic Biology.

To contact Xing Wang, email xingw@illinois.edu.

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

This story was written by Jonathan King, CCIL Communications Coordinator.