Acute myelogenous leukemia (AML) is a fatal blood cancer with high patient mortality. Daunorubicin and cytarabine are first-line chemotherapy for AML, with bone marrow transplantation in most cases. Recently, cancer immunotherapy has been challenged in AML and leukemia-niche myeloid cells are promising targets for the AML immunotherapy. Heme oxygenase 1 (HO1) is an antioxidative and cytoprotective enzyme inducing chemo-resistant AML and has been focused as an immune checkpoint molecule in tumor microenvironments. Herein, lipid-polymer hybrid nanoparticle (hNP) is loaded with tin mesoporphyrin (SnMP), a HO1-inhibitor, and non-covalently modified with an engineered antibody for leukemic cell-targeted delivery. HO1-inhibiting T-hNP (T-hNP/SnMP) enhances chemo-sensitivity in human leukemia cells. In a human AML-bearing orthotopic mouse model, intravenously injected T-hNP not only actively targets to human leukemia cells but passively targets to CD11b+ myeloid cells in a bone marrow niche. The T-hNP/SnMP enhances the chemo-therapeutic effect of daunorubicin and boosts immune response by reprogramming bone marrow myeloid cells resulting from the recruitment of the monocyte-lineage and induction of inflammatory genes. The ex vivo study demonstrates an enhanced immune response of HO1-inhibited bone marrow CD11b+ myeloid cells against apoptotic leukemia cells. Collectively, HO1-inhibiting dual cell-targeted T-hNP/SnMP has a strong potential as a novel therapeutic in AML.