Prussian Blue Nanozyme Potentiates Venetoclax Efficacy in Acute Myeloid Leukemia by Inducing a More Mature Phenotype.

INTRODUCTION

Acute Myeloid Leukemia (AML) is characterized by the clonal expansion of undifferentiated myeloid precursors and is associated with notably higher incidence and mortality rates in the elderly population. While the BCL-2 inhibitor Venetoclax has transformed the therapeutic landscape for patients with AML who were ineligible for intensive therapy, primary and acquired resistance remained major obstacles to durable responses.

METHODS

In this study, an ultra-small Prussian Blue nanozyme (USPBNP)-based "maturation-priming" strategy was investigated to enhance Venetoclax sensitivity. USPBNPs were synthesized and characterized for physicochemical properties and enzyme-mimetic activities. Their differentiation-inducing effects were evaluated in Venetoclax-sensitive MOLM-13 cells, acquired-resistant RMOLM-13 cells, primary-resistant OCI-AML3 cells, murine C1498 AML cells, an AML1-ETO/KITD816V murine transplant model, and primary human AML bone marrow mononuclear cells. Cellular maturation was assessed by morphological analysis and flow-cytometric detection of lineage-associated markers. Venetoclax sensitization was evaluated by apoptosis assays, mitochondrial membrane potential analysis, and detection of apoptosis-related proteins.

RESULTS

In vitro, USPBNPs effectively reshaped the leukemic phenotype, driving differentiation in MOLM-13, RMOLM-13, and OCI-AML3 AML cells, evidenced by the reduced nucleo-cytoplasmic ratio as well as up-regulated CD11b, CD14, CD235a and CD41a. The "maturation-priming" effects were also confirmed through cross-species models in C1498 murine AML cells and a refractory AML1-ETO/KITD816V murine transplant mice model in vivo and in human clinical specimen. This phenotypic maturation lowered the apoptotic threshold of Venetoclax, resulting in mitochondrial membrane potential collapse, Caspase-3 activation, and the down-regulation of the resistance-associated protein MCL-1.

CONCLUSION

These findings supported USPBNPs as a maturation-priming approach in AML models with distinct genetic backgrounds and Venetoclax resistance patterns. The combination of USPBNPs and Venetoclax coupled differentiation induction with apoptosis and might provide a potential strategy for improving Venetoclax responsiveness in AML.