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Acute myeloid leukemia (AML) is a common malignant heterogeneous hematopoietic disease with very low average 5-year survival rate due to the refractory feature and high rate of relapse. CD123 is highly expressed on multiple types of AML cells, especially leukemia stem cells, and closely associated with the poor prognosis of AML. Aiming to meet the urgent demand to targeted therapeutics for the refractory AML patients, herein we synthesize a CD123 antagonistic peptide (PO-6) loaded in nanomicelles ( m PO-6), and investigated its therapeutic effect and pharmacokinetics on a lab-established refractory AML mice model (AE & CKIT D816V ). It is shown that the PO-6 can effectively bind to the CD123 +  AML cells and the micellar formulation  m PO-6 increases the dissolution stability and the specific binding capacity. When injected intravenously,  m PO-6 significantly prolongs the survival of the refractory AML mice by interfering CD123/IL-3 axis, evidenced by the down regulation of phosphorylation of STAT5 and PI3K/AKT and the inhibition of activated NF-κB in the nucleus, as well as by the analysis results of next generation RNA-sequencing (RNA-seq) with the bone marrow of the AML mice. The antagonistic effect leads to the significantly reduction of AML cells infiltration in the bone marrow of the AML mice. In conclusion,  m PO-6 could provide a potent antagonistic therapeutic approach for targeted treatment of AML.   Supplementary Information  The online version contains supplementary material available at 10.1186/s13045-021-01206-y.

A novel CD123-targeted therapeutic peptide loaded by micellar delivery system combats refractory acute myeloid leukemia