Synergistic enhancement of ferroptosis via a multi-functional metal-coordinated nanoplatform for cancer therapy.

Hepatocellular carcinoma (HCC)is a highly heterogeneous and treatment-resistant malignancy, where conventional treatments are largely hindered by tumor microenvironment (TME) barriers. Ferroptosis, a non-apoptotic form of regulated cell death driven by Fenton reaction-mediated hydroxyl radical (•OH) generation and lipid peroxidation, has emerged as a promising strategy to overcome tumor resistance. However, ferroptosis efficiency in HCC is severely restricted by insufficient hydrogen peroxide (H₂O₂), elevated glutathione (GSH), and temperature-dependent reaction kinetics.To address these limitations, we developed pH-responsive nanoparticles (NPs) via Fe²⁺-coordinated indocyanine green (ICG) self-assembly, loaded with doxorubicin (DOX). This nanoplatform enhances ferroptosis through multiple mechanisms: DOX upregulates NADPH oxidase 4 (NOX4) expression, thereby increasing intracellular H₂O₂ levels; ICG, upon near-infrared (NIR) irradiation, synergistically induces photodynamic therapy (PDT)-mediated GSH depletion and photothermal therapy (PTT)-driven acceleration of the Fenton reaction, ultimately amplifying ferroptosis. This study demonstrates tumor microenvironment-responsive and synergistic drug delivery, effectively enhancing ferroptotic cancer therapy while reducing DOX- and Fe2⁺-induced toxicity in healthy tissues. Both in vitro and in vivo experiments confirm that this nanoplatform significantly enhances ferroptosis efficiency, overcomes tumor microenvironment limitations, and offers a promising strategy for HCC treatment.