RESEARCH @ THE UNIVERSITY OF ILLINOIS, URBANA-CHAMPAIGN
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).