All-Trans Retinoic Acid-Loaded Fe–N3–Se Single-Atom Nanozymes Enable Redox-Guided Differentiation Therapy for Acute Myeloid Leukemia

Abstract Differentiation blockade is a defining hallmark of acute myeloid leukemia (AML). While all-trans retinoic acid (ATRA)-based differentiation therapy is curative in acute promyelocytic leukemia (APL), its efficacy in non-APL AML remains limited, and the determinants of differentiation responsiveness beyond APL are poorly understood. Here, we identify redox homeostasis reprogramming as a decisive and previously underappreciated regulator of differentiation therapy efficacy in AML and establish nanozyme-enabled redox modulation as a generalizable framework to restore differentiation competence. We rationally design a Fe–Se dual-atom nanozyme that reconstructs key catalytic features of natural glutathione peroxidase, enabling controlled and homeostatic regulation of intracellular oxidative stress. When combined with ATRA, this redox-guided strategy reinstates differentiation-associated transcriptional programs, suppresses leukemic stemness, and overcomes intrinsic differentiation resistance independently of APL-specific oncogenic drivers. Efficacy is demonstrated in human AML xenograft models and a hoxa9-driven differentiation-arrest zebrafish model. Collectively, this work defines redox regulation as an actionable control point for extending differentiation-based therapies beyond genetically restricted AML subtypes.