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<p>Acute myeloid leukemia (AML) is characterized by differentiation arrest and apoptosis resistance, frequently with mitochondrial dysfunction and aberrant heat shock protein 60 (HSP60) overexpression as key drivers of malignant progression. Platinum-based nanozymes exhibit multi-enzymatic activity but lack organelle specificity, limiting their therapy efficacy. Based on that there are abundant HSP60 in mitochondrial, we constructed a peptide-conjugated nanozyme PtNPs-P17 by conjugation platinum nanoparticle (PtNPs) and HSP60-targeting peptide P17. It was shown that PtNPs-P17 retained intrinsic oxidase (OXD), peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT)-like activities while acquiring the targeting ability. In the myeloperoxidase (MPO)-positive AML cell line MOLM-13, PtNPs-P17 specifically localized to mitochondria in cells, significantly increasing the production of reactive oxygen species (ROS), oxygen and especially singlet oxygen due to its multi-enzymatic redox regulatory function, which disrupted mitochondrial membrane potential and triggered mitophagy evidenced by the elevated LC3BII/actin ratio and LC3B-mitochondria co-localization. Moreover, PtNPs-P17 induced dual inhibition of mitochondrial respiration and glycolysis, leading to total NAD levels reduced. These metabolic perturbations together resulted in the differentiation of the AML cells, with up-regulated levels of CD235a, CD11b, and CD41a, and enhanced apoptosis. In a refractory AML mouse model, PtNPs-P17 significantly down-regulated the HSP60 expression while reduced spleen GFP<sup>+</sup> leukemia cells, suggesting significantly enhanced anti-leukemia effects compared to PtNPs. In conclusion, it was demonstrated that PtNPs-P17 targeted mitochondrial HSP60 to induce mitophagy by orchestrating multi-enzymatic redox regulation and mitochondrial reprogramming, thereby overcoming AML differentiation block and apoptosis resistance. This study provides a novel AML therapy option via precise mitochondrial targeting and metabolic intervention, highlighting the translational potential of HSP60-targeted multi-enzyme nanozymes.</p> Graphical abstract <p></p>

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Heat shock protein 60-targeted peptide-conjugated platinum nanozyme: redox regulation by multi-enzyme activities induces mitochondrial reprogramming and acute leukemia cells fate switch

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • Jing Yao,
  • Yanyan Li,
  • Yiling Meng,
  • Tao Wang,
  • Jie Meng,
  • Jian Liu,
  • Tao Wen,
  • Haiyan Xu

摘要

Acute myeloid leukemia (AML) is characterized by differentiation arrest and apoptosis resistance, frequently with mitochondrial dysfunction and aberrant heat shock protein 60 (HSP60) overexpression as key drivers of malignant progression. Platinum-based nanozymes exhibit multi-enzymatic activity but lack organelle specificity, limiting their therapy efficacy. Based on that there are abundant HSP60 in mitochondrial, we constructed a peptide-conjugated nanozyme PtNPs-P17 by conjugation platinum nanoparticle (PtNPs) and HSP60-targeting peptide P17. It was shown that PtNPs-P17 retained intrinsic oxidase (OXD), peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT)-like activities while acquiring the targeting ability. In the myeloperoxidase (MPO)-positive AML cell line MOLM-13, PtNPs-P17 specifically localized to mitochondria in cells, significantly increasing the production of reactive oxygen species (ROS), oxygen and especially singlet oxygen due to its multi-enzymatic redox regulatory function, which disrupted mitochondrial membrane potential and triggered mitophagy evidenced by the elevated LC3BII/actin ratio and LC3B-mitochondria co-localization. Moreover, PtNPs-P17 induced dual inhibition of mitochondrial respiration and glycolysis, leading to total NAD levels reduced. These metabolic perturbations together resulted in the differentiation of the AML cells, with up-regulated levels of CD235a, CD11b, and CD41a, and enhanced apoptosis. In a refractory AML mouse model, PtNPs-P17 significantly down-regulated the HSP60 expression while reduced spleen GFP+ leukemia cells, suggesting significantly enhanced anti-leukemia effects compared to PtNPs. In conclusion, it was demonstrated that PtNPs-P17 targeted mitochondrial HSP60 to induce mitophagy by orchestrating multi-enzymatic redox regulation and mitochondrial reprogramming, thereby overcoming AML differentiation block and apoptosis resistance. This study provides a novel AML therapy option via precise mitochondrial targeting and metabolic intervention, highlighting the translational potential of HSP60-targeted multi-enzyme nanozymes.

Graphical abstract