Bone marrow-targeted LOXL2 inhibitor-loaded yolk-shell nanoparticle overcomes extracellular matrix-mediated chemotherapy resistance in acute myeloid leukemia

The adhesion of leukemic cells to the extracellular matrix (ECM) in the bone marrow microenvironment is a critical factor contributing to the high rates of chemotherapeutic resistance in acute myeloid leukemia (AML) chemotherapy. In this study, preventing AML cell-ECM adhesion using bone marrow-targeted LOXL2 inhibitor (LOXL2i)-loaded yolk-shell nanoparticles (LOXL2i DSS6-NPs) remarkably enhances the AML chemotherapeutic efficacy. Firstly, hydrophilic LOXL2i is successfully encapsulated in the Collagen I-hydrogel yolk of nanoparticles composed of Collagen I and PEG-PLGA with high drug loading content. The inhibition of LOXL2 with LOXL2i-loaded NPs disrupts the integrity of Collagen structure in ECM and blocks contact-dependent interactions between AML cells and ECM in vitro. LOXL2i-loaded NPs also contribute to the penetration of nanoparticles in stroma-rich spheroids. LOXL2i-loaded DSS6-NPs can remodel the Collagen crosslinking and decrease the deposition of ECM in vivo. LOXL2i-loaded DSS6-NPs sensitize AML to cytarabine treatment and greatly reduce the burden of leukemia in murine AML model. Overall, bone marrow-targeted LOXL2i-loaded yolk-shell nanoparticles represent an effective strategy to overcome AML chemotherapy resistance via blocking AML cell-ECM adhesion in the bone marrow.