Targeted drug delivery is poised to improve cancer therapy, for which synthetic DNA can serve as targeting ligands (for example, aptamers) or drug nanocarriers. Inspired by natural DNA adducts, we report synthetic drug-DNA adducts (DDAs) for targeted anticancer drug delivery. Multiple copies of anthracycline drugs were site specifically (on deoxyguanosine) conjugated on each DNA, enabling programmable design of DNA and drugs for DDA preparation. DDAs were nuclease-resistant and stable for storage, yet gradually released drugs at physiological temperature. DDAs maintained DNA functionalities, including hybridizationmediated DNA nanoadduct formation and aptamer-mediated target recognition and targeted drug delivery into cancer cells. In a tumor xenograft mouse model, doxorubicin-aptamer adducts significantly inhibited target tumor growth while reducing the side effects. Using histopathological analysis and in situ immunohistochemical analysis of caspase-3 cleavage in mouse tumor and heart, DDAs were confirmed to have a potent antitumor efficacy while reducing tissue deformation and apoptosis in the heart, thus providing a new therapeutic avenue to prevent cardiomyopathy, the most dangerous side effect of doxorubicin leading to heart failure. Overall, DDAs are promising for scale-up production and clinical application in targeted anticancer drug delivery.