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Herein, the designer DNA architecture (DDA)\u2010templated drug conjugates (DDA\u2010DCs) customized are presented to deliver daunorubicin (Dau) specifically and potently to a subset of CSCs: acute myeloid leukemia\u00a0(AML) leukemic stem cells (LSCs) that often maintain minimal residual disease (MRD) and cause relapse. These DDA\u2010DCs target LSCs via CD117\u2010 and CD123\u2010binding aptamers: aptamers that when used alone disrupts the MAP Kinase and apoptosis signaling pathways, leading to a 40% reduction in cell viability over 72 h. These aptamers, when loaded with dsDNA\u2010intercalating Dau and docked to DDA platforms, exhibit potent and selective cytotoxicity against CD117\n                    <jats:sup>+<\/jats:sup>\n                    \/CD123\n                    <jats:sup>+<\/jats:sup>\n                    AML cells, achieving a reduction in effective drug dosage by 500\u2010fold ex vivo and up to 10\u2010fold in vivo AML models. These DDA\u2010DC strategy confers many advantages over other targeted therapies, such as selective cell targeting based on cell surface biomarker profiles (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\u2010target effects.\n                  <\/jats:p>","DOI":"10.1002\/adfm.202425394","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T03:38:31Z","timestamp":1738899511000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Engineering Novel DNA Nanoarchitectures for Targeted Drug Delivery and Aptamer Mediated Apoptosis in Cancer Therapeutics"],"prefix":"10.1002","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9745-8138","authenticated-orcid":false,"given":"Abhisek","family":"Dwivedy","sequence":"first","affiliation":[{"name":"Department of Bioengineering Grainger College of Engineering University of Illinois at Urbana\u2010Champaign  Urbana IL 61801 USA"},{"name":"Holonyak Micro &amp; Nanotechnology Lab Grainger College of Engineering University of Illinois at Urbana\u2010Champaign  Urbana IL 61801 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8334-1010","authenticated-orcid":false,"given":"Dhyanesh","family":"Baskaran","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering Grainger College of Engineering University of Illinois at Urbana\u2010Champaign  Urbana IL 61801 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaurav","family":"Sharma","sequence":"additional","affiliation":[{"name":"Atom Bioworks Inc.  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