Nanozyme-Powered Immunotherapy via Concurrent Niche Disruption and Checkpoint Blockade for Acute Myeloid Leukemia

Acute myeloid leukemia (AML) relapse and drug resistance remain major causes of mortality in hematologic malignancies, driven in part by CXCR4/CXCL12-mediated homing and retention of leukemic cells within the bone marrow niche, as well as immune evasion mechanisms that enable their persistent survival. Here, we report a Cascade Catalysis Fe₃O₄@Pt nanozyme platform co-functionalized with a CXCR4 antagonist and anti-PD-L1 (aPD-L1) antibody for synergistic therapy of drug-resistant AML. This nanoplatform simultaneously disrupts the CXCL12/CXCR4 axis to suppress AML cell homing and bone marrow infiltration, while blocking the PD-1/PD-L1 immune checkpoint to overcome immune evasion and enhance T cell-mediated cytotoxicity against leukemic cells. Following lysosomal internalization, the Fe₃O₄@Pt nanozyme exhibits cascade catalytic activity under mildly acidic conditions, generating highly cytotoxic reactive oxygen species (ROS) to effectively eradicate drug-resistant AML cells while minimizing damage to normal counterparts. In vitro and in vivo studies demonstrate that this nanoplatform effectively suppresses AML progression by preventing bone marrow engraftment and systemic dissemination to peripheral organs, including the spleen, lungs, and liver. Concurrently, it enhances antitumor immune responses via T cell activation, resulting in markedly improved therapeutic efficacy and significantly prolonged survival in AML-bearing mice. Overall, this work presents a nanozyme-based therapeutic strategy that combines microenvironment-responsive catalytic therapy, dual signaling axis blockade, and immune modulation, offering a promising approach for overcoming relapse and drug resistance in AML. STATEMENT OF SIGNIFICANCE: This study presents a multifunctional nanozyme-based immunotherapeutic platform that simultaneously targets leukemia cell survival, bone marrow microenvironment protection, and immune evasion in acute myeloid leukemia (AML). By integrating Fe₃O₄@Pt nanozyme-mediated catalytic ROS generation, CXCR4 blockade, and PD-L1 immune checkpoint inhibition, this system enables coordinated disruption of leukemic niche interactions and restoration of antitumor immunity. The findings provide a generalizable strategy for combining catalytic nanomedicine with microenvironment and immune modulation to overcome relapse and drug resistance in hematological malignancies.