Small molecule pharmaceutical treatment of cancer faces several challenges, including chemoresistance, non-ideal pharmacokinetics/pharmacodynamics, and systemic toxicity. While synthetic nano-scale drug delivery systems have risen to the challenge by improving PK/PD and shielding the immune system from toxic chemotherapeutics, limited scalability and toxicity remain obstacles due to the materials used in their manufacture and the behavior of such materials in the body. Rarely are these nanoparticles produced without the incorporation of several labor-, time-, and cost-intensive production and purification processes, making them expensive to synthesize and difficult to scale-up for clinical or commercial use. Furthermore, disappointingly low therapeutic payload is a common concern. Thus, we look towards natural biopolymers and wonder if it is possible to simply use nucleic acids themselves as a drug delivery vehicle for cancer chemotherapies. DNA fragments are readily produced from a natural source and offer the desired properties for the delivery of small molecule therapeutics. A model cancer chemotherapeutic was complexed with DNA fragments in a scalable and cost-effective manner with high drug-loading. The resulting nano-scale complexes demonstrated improved anti-cancer efficacy with substantially lowered toxicity in vitro and in vivo, in comparison with free drug and a commercially available liposomal formulation. Also highlighted is the characterization of the complexes at a molecular level and a mechanistic study on the complexes’ interactions with cancer cells in vitro and in vivo. The results of this work encourage an elegant and simple approach to drug formulation that utilizes the natural properties of nucleic acids to address the fundamental challenges in cancer chemotherapy. Finally, this new formulation may offer immediate implications for rapid clinical translation and commercialization.