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

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.