Biomimetic, Hypoxia‐Responsive Nanoparticles Overcome Residual Chemoresistant Leukemic Cells with Co‐Targeting of Therapy‐Induced Bone Marrow Niches

Abstract Chemoresistance conferred by leukemia propagating cells (LPCs) in a therapy‐induced niche (TI‐niche) within the bone marrow is one of the main obstacles in leukemia treatment. Effective approaches to circumvent the TI‐niche protection and to eliminate the resident LPCs remain to be exploited. Here, developed is a niche‐targeted nanosystem using leukemic cell membrane‐coated mesoporous silica nanoparticles (DA azo @CMSN) for co‐delivering daunorubicin for leukemia cell chemotherapy and a TGFβRII neutralizing antibody (aTGFβRII) to block niche signaling. DA azo @CMSN effectively targets the TI‐niche. Through an azobenzene‐based hypoxia‐responsive linker, sequential delivery of the two active molecules overcomes niche‐mediated chemoresistance, attenuates systemic burden, and prolongs survival in a mouse model of leukemia. This work demonstrates a proof‐of‐principle for biomimetic and microenvironment‐activated multiplexed nanoparticulate drug delivery strategies for overcoming therapy‐induced chemoresistance in leukemia.