<p>Chemotherapy is the primary clinical treatment for leukemia, while its effectiveness is often limited due to undesired off-target effects and the reduced sensitivity of leukemia cells to chemotherapeutic agents. Therapies capable of targeting the bone marrow and addressing the acidic tumor microenvironment are anticipated to improve treatment efficacy. Here, we presented biomimetic cell membrane-decorated calcium carbonate nanoparticles co-loaded with asparaginase and metformin (AMNPs@CM) for bone marrow-targeted therapy of leukemia. The biomimetic cell membrane coating facilitated significant accumulation of AMNPs@CM in the bone marrow, where the nanoparticles released the payloads in response to the acidic tumor microenvironment. The released asparaginase and metformin could synergically induce mitochondrial dysfunction in leukemia cells, leading to inhibited cell proliferation and enhanced apoptosis. Thus, our stratagem could effectively inhibit tumor burden and prolong survival in a C1498 leukemia-bearing mouse model. These results indicate the potential of the AMNPs@CM as a bone marrow-targeted delivery platform for combination therapy in the treatment of leukemia.</p> Graphical Abstract <p></p>