Polydopamine@Iron/Ellagic Acid Nanoparticles: Self-Reinforcing Ferroptosis–Apoptosis Synergy Disrupts Energy Metabolism for Melanoma Therapy

Melanoma, the most aggressive form of skin cancer, presents significant therapeutic challenges due to its high metastatic propensity and resistance to conventional therapies. To address these limitations, we engineered a polyethylene glycol (PEG)-modified nanoplatform by integrating a metal-polyphenol network (composed of ellagic acid (EA) and ferrous iron (Fe²⁺)) with polydopamine nanoparticles (PDA NPs), termed PDA@Fe²⁺/EA-PEG (PFE-PEG) NPs. We demonstrated that PFE-PEG NPs exhibited excellent Fenton-like activity, photothermal conversion capability, and tyrosinase inhibitory activity. <i>In vitro</i> studies demonstrated that exogenous iron ions in PFE-PEG NPs induced ferroptosis through glutathione (GSH) depletion and glutathione peroxidase 4 (GPX4) inactivation, whereas EA-triggered caspase-mediated apoptosis and concurrently suppressed melanin synthesis via its intrinsic pharmacological activity. Notably, PDA NPs not only mediated photothermal ablation under NIR irradiation but also amplified Fe²⁺/EA network dissociation by generating localized hyperthermia, thereby creating a self-reinforcing therapeutic loop that enhanced both ferroptosis and apoptosis. <i>In vivo</i> experiments demonstrated the potent inhibition of melanoma growth and metastasis by PFE-PEG NPs. Mechanistic analysis further revealed that the PFE-PEG NPs suppressed melanoma glycolysis, thereby disrupting metabolic homeostasis in the tumor microenvironment. This work establishes a multimodal therapeutic strategy that coactivates ferroptosis and apoptosis while disrupting tumor metabolic dependencies, thereby achieving synergistic antitumor efficacy against melanoma.