Bone marrow microenvironment-targeted yolk-shell nanoparticle enhances acute myeloid leukemia chemotherapy by preventing endothelial cell/ECM-mediated adhesion

Leukemic cell adhesion to the vascular endothelium and extracellular matrix (ECM) in the bone marrow is a major determinant for frequent drug resistance and relapse in acute myeloid leukemia (AML) chemotherapy. Here, we found that blocking cell–cell and cell-ECM adhesion with DSS6 peptide-modified ginsenoside Rh2 (Rh2) /LOXL2 inhibitor (LX2i) co-loaded yolk-shell nanoparticles (DSS6-NPs) greatly improve the AML chemotherapeutic efficacy. We constructed a collagen I/PEG-PLGA NP with a unique yolk-shell structure to encapsulate hydrophilic LX2i in the collagen I hydrogel-formed yolk, and hydrophobic Rh2 in the PLGA shell. Rh2 in yolk-shell NP reduces AML cell retention in heterotypic spheroids via inhibiting AML cell adhesion to endothelial cells. LOXL2 inhibition prevents contact-dependent interactions between AML cells and ECM. Targeting bone marrow microenvironment-driven adhesion with Rh2/LX2i NPs sensitizes AML cells to cytarabine treatment in a 3D vascularized hydrogel model in vitro . The combination of cytarabine and Rh2/LX2i DSS6-NPs restores the competitive advantage of hematopoietic stem cells over leukemic stem cells, and remodels collagen crosslinking to increase NP penetration in the bone marrow in vivo . Rh2/LX2i DSS6-NPs significantly enhanced the efficacy of cytarabine in a murine AML model. This study provides an effective strategy for developing bone marrow microenvironment-targeted therapeutics for improving AML chemotherapy.