Engineered cell membrane vesicles loaded with lysosomophilic drug for acute myeloid leukemia therapy via organ-cell-organelle cascade-targeting.

Abstract

Acute myeloid leukemia (AML) presents significant treatment challenges due to the severe toxicities and limited efficacy of conventional therapies, highlighting the urgency for innovative approaches. Organelle-targeting therapies offer a promising avenue to enhance therapeutic outcomes while minimizing adverse effects. Herein, inspired that primary AML cells are enriched with lysosomes and sensitive to lysosomophilic drugs (e.g., LLOMe), we developed a smart nanodrug (Cas-CMV@LM) including the engineered cell membrane vesicles (CMVs) nanocarrier and the encapsulated drug cargo LLOMe (LM). Briefly, the nanodrug with organ-cell-organelle cascade-targeting function could firstly home to the bone marrow guided by CMVs derived from CXCR4-overexpressing bone marrow mesenchymal stem cells (BMSC), subsequently target leukemia cells via CD33 and CD123 aptamers anchored on the vesicles, eventually precisely attack the lysosomes of leukemia cells. Consequently, Cas-CMV@LM specifically inhibited leukemia cell proliferation and triggered necroptosis in vitro. Importantly, the cascade-targeting nanodrug displayed high biosafety and significantly impeded leukemia progression in AML patient-derived xenograft (PDX) model. Collectively, this study provides a paradigm for precision leukemia treatment from the perspective of targeting organelle-lysosome.