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<p>Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation (LPO), has emerged as a promising strategy for cancer therapy but remains limited by insufficient hydrogen peroxide (H₂O₂), restricted catalytic iron availability, and the extremely short lifetime of hydroxyl radicals (·OH) in the tumor microenvironment. Here, we report a self-assembled nano-prodrug designed to amplify oxidative stress through coordinated reactive oxygen species (ROS)-reactive nitrogen species (RNS) cascades. Transcriptomic analyses of melanoma cohorts revealed that the redox enzyme NAD(P)H: quinone oxidoreductase-1 (NQO1) is frequently upregulated and associated with oxidative stress and ferroptosis-related transcriptional programs, suggesting a potential redox vulnerability that can be therapeutically exploited. Guided by this observation, a glutathione-responsive nanoplatform (HFSAL) was constructed from a disulfide-bridged ferrocene–arginine scaffold (Fc-SS-Arg) with β-lapachone (β-lapa) co-loaded and hyaluronic acid coating for tumor-targeted delivery. Upon intracellular activation, β-lapa undergoes NQO1-mediated redox cycling to generate H₂O₂, which is further converted into ·OH through ferrocene-catalyzed Fenton reactions. Meanwhile, arginine-derived nitric oxide (NO) reacts with ROS intermediates to form highly reactive peroxynitrite (ONOO⁻), thereby amplifying oxidative damage and extending the effective range of redox stress. In addition, NO-mediated vascular remodeling alleviates tumor hypoxia and enhances intratumoral drug accumulation. Consequently, the HFSAL nano-prodrug effectively induces synergistic ferroptosis and apoptosis, leading to significant tumor growth inhibition and metastasis suppression in vivo with favorable biosafety. This work presents a redox-amplifying nano-prodrug strategy that exploits NQO1-associated metabolic vulnerability to enhance ferroptosis-based cancer therapy.</p> Graphical Abstract <p></p>

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Cascade-activatable nano-prodrug amplifies ROS-RNS signaling to target NQO1-associated redox vulnerability for melanoma therapy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月3日

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  • Honglin Tang,
  • Chongzhi Wu,
  • Wei Wang,
  • Xi Cheng,
  • Yong Dong,
  • Zhiyuan Gao,
  • Pengfei Chen,
  • Xin Xie,
  • Yong Huang,
  • Lihe Sun,
  • Bowen Li,
  • Da Li

摘要

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation (LPO), has emerged as a promising strategy for cancer therapy but remains limited by insufficient hydrogen peroxide (H₂O₂), restricted catalytic iron availability, and the extremely short lifetime of hydroxyl radicals (·OH) in the tumor microenvironment. Here, we report a self-assembled nano-prodrug designed to amplify oxidative stress through coordinated reactive oxygen species (ROS)-reactive nitrogen species (RNS) cascades. Transcriptomic analyses of melanoma cohorts revealed that the redox enzyme NAD(P)H: quinone oxidoreductase-1 (NQO1) is frequently upregulated and associated with oxidative stress and ferroptosis-related transcriptional programs, suggesting a potential redox vulnerability that can be therapeutically exploited. Guided by this observation, a glutathione-responsive nanoplatform (HFSAL) was constructed from a disulfide-bridged ferrocene–arginine scaffold (Fc-SS-Arg) with β-lapachone (β-lapa) co-loaded and hyaluronic acid coating for tumor-targeted delivery. Upon intracellular activation, β-lapa undergoes NQO1-mediated redox cycling to generate H₂O₂, which is further converted into ·OH through ferrocene-catalyzed Fenton reactions. Meanwhile, arginine-derived nitric oxide (NO) reacts with ROS intermediates to form highly reactive peroxynitrite (ONOO⁻), thereby amplifying oxidative damage and extending the effective range of redox stress. In addition, NO-mediated vascular remodeling alleviates tumor hypoxia and enhances intratumoral drug accumulation. Consequently, the HFSAL nano-prodrug effectively induces synergistic ferroptosis and apoptosis, leading to significant tumor growth inhibition and metastasis suppression in vivo with favorable biosafety. This work presents a redox-amplifying nano-prodrug strategy that exploits NQO1-associated metabolic vulnerability to enhance ferroptosis-based cancer therapy.

Graphical Abstract