RESEARCH @ THE UNIVERSITY OF ILLINOIS, URBANA-CHAMPAIGN
Aptamer Chiral Arrangement on DNA Origami Control Cellular Outcomes
We combined DNA origami and test the hypothesis that different spatial ligand patterning can dictate cellular uptake behavior. We designed rigid DNA origami nanotubes and decorated them with multiple identical aptamers positioned at defined locations on the tube surface, allowing us to construct left-handed (L-CAP) and right-handed (R-CAP) chiral architectures without altering chemical composition. Structural fidelity and handedness were validated through computational design and high-resolution structural characterization, while receptor engagement and uptake were evaluated using fluorescence microscopy and quantitative cellular internalization assays. By correlating structural chirality with receptor organization at the plasma membrane, we observed that only L-CAP configuration effectively induces receptor dimerization, leading to robust endocytic internalization. The mirror-image R-CAP structure failed to induce dimer formation and largely remained surface-associated. This systematic, geometry-controlled approach allowed us to directly link three-dimensional ligand arrangement to biological function, thereby experimentally validating our hypothesis.
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Figure: Left-handed Chiral Aptamer Pattern (L-CAP) on DNA-Origami exhibits enantioselective receptor dimerization and cellular uptake.
Our findings have important implications for precision nanomedicine. Chirality-encoded DNA nanostructures offer a powerful strategy for selective drug delivery, diagnostics, and receptor-specific signaling control, while minimizing nonspecific uptake. More broadly, this work establishes geometry as a programmable biological signal, opening new directions for designing therapeutics that regulate cell behavior through nanoscale spatial organization rather than chemistry alone (Read the full text here).
Engineering DNA Nanoarchitectures for Precision Cancer Therapeutics
While innovative cancer therapies such as vaccines and CAR-T cells are gaining momentum, their variable efficacy and uncertain long-term effects have sustained chemotherapy’s central role in cancer treatment. However, conventional chemotherapy is often limited by off-target toxicity and poor tumor specificity, particularly in diffuse malignancies like acute myeloid leukemia (AML), where relapse is frequently driven by treatment-resistant leukemic stem cells (LSCs).
Figure: Schematic overview of the design and function of the Designer DNA Architecture–Drug Conjugate (DDA-DC).
In our recent work, we identified a distinct biomarker combination—CD117 and CD123—selectively expressed on AML LSCs, and developed single-stranded DNA (ssDNA) aptamers to target them. Notably, some of these aptamers independently induced apoptosis in AML cells (Kasumi-1) by activating intrinsic cell death pathways. Leveraging their DNA-binding capability, these aptamers also facilitated efficient delivery of the chemotherapeutic drug daunorubicin without requiring complex chemical modifications. To enhance selective targeting, we engineered a Designer DNA Architecture (DDA) loaded with daunorubicin-conjugated aptamers specific to CD117 and CD123, forming DDA-Drug Conjugates (DDA-DCs). These constructs demonstrated precise targeting and effective elimination of AML cells in both ex vivo and in vivo models, while reducing the required daunorubicin dosage by over 500-fold ex vivo and 10-fold in vivo. Building on these results, we are now developing advanced DDA-DCs for solid tumors, using AND Gate logic, we are engineering pH-responsive systems (Read the full text here).