Bone marrow microenvironment-responsive polymeric-drug/siRNA regulates leukemia stem cells assisting for prevention of AML relapse.

Acute myeloid leukemia (AML) remains a formidable hematological malignancy with a poor prognosis, largely due to the limited success of existing treatments in effectively targeting leukemia stem cells (LSCs). These cells are adept at migrating into hypoxic niches within the bone marrow, thereby evading chemotherapeutic agents and retaining their stem-like properties. This evasion facilitates their survival and subsequent regeneration following treatment, significantly contributing to disease relapse and highlighting the need for novel therapeutic interventions. Herein, we present the development of an innovative polymer-drug/siRNA delivery system engineered to respond to hypoxic microenvironments within the bone marrow. This system enables the precision co-delivery of the CXCR4 antagonist plerixafor and siRNA targeting mitochondrial fission protein 1 (Fis1), which induces mitophagy to LSCs. By disrupting the CXCR4/CXCL12 axis and downregulating Fis1 expression, the system effectively impedes LSCs migration and concurrently suppresses mitochondrial autophagy, thereby diminishing the stemness of LSCs. Our findings demonstrate that this dual-action delivery system (PPLazo/siFis1@C) significantly enhances the efficacy of conventional chemotherapeutic agents by concurrently inhibiting LSCs migration and impairing stemness. This integrative therapeutic strategy, which targets both the displacement and self-renewal capacity of LSCs, holds significant promise for improving outcomes in AML relapse treatment.