Engineering Novel DNA Nanoarchitectures for Targeted Drug Delivery and Aptamer Mediated Apoptosis in Cancer Therapeutics
The specific and potent delivery of anticancer drugs to targeted cancer stem cells (CSCs) remains a critical need to maximize on-target, on-tumor effects while minimizing on-target, off-tumor toxicities. Herein, we present our Designer DNA Architecture (DDA)-templated Drug Conjugates (DDA-DCs) customized to deliver daunorubicin (Dau) specifically and potently to a subset of CSCs: acute myeloid leukemia (AML) leukemic stem cells (LSCs) that often maintain minimal residual disease (MRD) and cause relapse. Our DDA-DCs targeted LSCs via CD117- and CD123-binding aptamers: aptamers that when used alone disrupted the MAP Kinase and Apoptosis signaling pathways, leading to a 40% reduction in cell viability over 72 hours. These aptamers, when loaded with dsDNA-intercalating Dau and docked to DDA platforms, exhibited potent and selective cytotoxicity against CD117<sup>+</sup>CD123<sup>+</sup> AML cells, achieving a reduction in effective drug dosage by 500-fold <i>ex vivo</i> and up to 10-fold <i>in vivo</i> AML models. Our DDA-DC strategy confers many advantages over other targeted therapies, such as selective cell targeting based on cell surface biomarker <b><i>profiles</i></b> (not just individual biomarkers that are often expressed by healthy tissues), titratable affinity, pattern matching, multiplexing, multidrug delivery, and target cell drug sensitization. The combination of these features yields superior anticancer efficacies with minimal off-target effects.
Authors
- Zackary Zimmers (ORCID: https://orcid.org/0000-0001-6900-3304)
- Ichrak Hayah (ORCID: https://orcid.org/0000-0002-0783-9672)
- Dhanush Gandavadi (ORCID: https://orcid.org/0009-0000-3063-4408)
- Mengxi Zheng (ORCID: https://orcid.org/0000-0002-1625-6663)
- Abhisek Dwivedy (ORCID: https://orcid.org/0000-0001-9745-8138)
- Yusheng Liu (ORCID: https://orcid.org/0000-0001-7595-5061)
- Joonsu Han (ORCID: https://orcid.org/0000-0002-7794-0661)
- Sherwood Yao (ORCID: https://orcid.org/0000-0002-2409-289X)
- Tshepo Mafokwane (ORCID: https://orcid.org/0000-0003-4069-2294)
- Abhichart Krissanaprasit (ORCID: https://orcid.org/0000-0001-6914-393X)
- Wei Hong (ORCID: https://orcid.org/0000-0001-7866-9917)
- Jeremy J. Decker (ORCID: https://orcid.org/0009-0006-2567-6279)
- Xiaohe Jin (ORCID: https://orcid.org/0000-0003-1497-8037)
- Xing Wang (ORCID: https://orcid.org/0000-0001-9930-3287)
- Hua Wang (ORCID: https://orcid.org/0000-0002-1157-8786)
- Gaurav Sharma (ORCID: https://orcid.org/0009-0006-5982-433X)
- Neha Chauhan (ORCID: https://orcid.org/0000-0002-7315-0080)
- Dhyanesh Baskaran
- Adam D. Friedman
- Keith Fraser (ORCID: https://orcid.org/0009-0004-5679-6105)
Institutions
- Mohammed V University (MA)
- University of Illinois Urbana-Champaign (US)
- University of South Africa (ZA)
- Rensselaer Polytechnic Institute (US)
- Urbana University (US)
- BioWorks (United States) (US)
Publication Details
- Journal
- Advanced Functional Materials
- Published
- 2025-02-07
- DOI
- https://doi.org/10.1002/adfm.202425394
- Citations
- 14
- Primary Topic
- Advanced biosensing and bioanalysis techniques
- Type
- article
- Field-Weighted Citation Impact
- 11.28
Funders
- National Science Foundation
- National Institutes of Health
- National Institute of Biomedical Imaging and Bioengineering