Approximately 150,000 Americans will be diagnosed with B-cell malignancies in 2013. Although treatment strategies exist, the disease is incurable due to development of drug resistance demanding novel therapeutic approaches. DNA origami nanostructures loaded with intercalating drugs were reported to circumvent drug resistance in MCF-7 breast cancer cells. We build on these results to evaluate how design parameters affect drug-loading efficiency and cytotoxicity in HL-60 drug resistant human B-cells. Here, 6-,12-, and 18-helix bundle honeycomb lattice structures, and a square lattice-based 16-helix bundle loaded with the intercalating drug daunorubicin were employed to evaluate whether surface area, density, or lattice conformation affected drug-loading efficiency and cytotoxicity. The 6-,and 12-helix bundles, and square 16 helix bundle had the highest loading efficiency, while daunorubicin-loaded 16-helix bundles most effectively killed drug resistant HL-60 cells suggesting surface area and lattice structure are critical for cytotoxicity. Future studies will evaluate structure cellular uptake and targeting via antibodies.