Acute myeloid leukemia (AML) is the most common acute leukemia in adults and a very serious disease. Most AML cells arise from a group of special stem cells, named leukemia stem cells (LSCs). One major reason for treatment failure is that LSCs are relatively resistant to current treatments. Although most leukemia cells are killed by treatment, resistant LSCs will survive to regenerate additional leukemia cells and cause a recurrence of leukemia. Recently, we have developed a small molecule that can recognize and bind to AML LSCs. We have also developed tiny particles named nanomicelles. These nanomicelles have a size of about 1-2/100th of one micron (one millionth of a meter), and can be loaded with chemotherapy drug called daunorubicin that can kill LSCs. In this project, we will coat the drug-loaded nanomicelles with small molecules that specifically bind and kill LSCs. In patient’s body, these drug-loaded nanomicelles will work like “smart bombs”, and deliver a high concentration of daunorubicin to kill LSCs. Over the last one year, we found that these LSC-targeting nanomicelles could target and kill LSC more efficiently that free daunorubicin or nanomicelles that do not target LSC. We also found that, compared to free daunorubicin commonly used in the treatment of AML now, daunorubicin in nanomicelles could raise the blood daunorubicin concentration by more than 20 times. This is clinically significant as leukemia cells and LSC are located inside blood vessels and bone, and have direct contact with blood. Therefore, increase in blood daunorubicin concentration may represent more efficiency in killing leukemia and LSC.