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

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.