An oxygen-independent Ir(III) complex photodynamic system with glutathion-threshold activation for synergistic redox-epigenetic breast cancer therapy.

Abstract

Breast cancer therapy remains constrained by poor tumor selectivity, adaptive drug resistance, and a narrow therapeutic window. Existing small-molecule inhibitors and targeted protein degradation strategies often suffer from insufficient tumor specificity, whereas photodynamic therapy (PDT) is compromised in hypoxic, glutathione (GSH)-rich tumors. Herein, Ir-F-GSH-JQ1 is developed as a GSH-gated iridium(III) theranostic agent that couples activation-reported phosphorescence imaging with redox-epigenetic synergistic therapy (REST) by integrating a GSH-activatable photosensitizer and a bromodomain-containing protein 4 (BRD4)-targeting JQ1 ligand. A 2-fluoro-4-nitrophenylsulfonyl trigger remains largely inert at physiological GSH concentrations (0.1-0.5 mM) but undergoes selective cleavage in GSH-rich tumors (∼10 mM), enabling tumor-specific activation and intracellular GSH depletion. The activated iridium(III) complex generates reactive oxygen species through a hypoxia-tolerant Type I pathway, disrupts redox homeostasis, promotes lipid peroxidation, downregulates glutathione peroxidase 4 (GPX4), and induces ferroptosis. Meanwhile, JQ1 ligand promotes nuclear accumulation and BRD4-targeted epigenetic intervention, which cooperates with oxidative stress to drive tumor cell killing and senescence. In breast tumor models, Ir-F-GSH-JQ1 enables GSH-activated luminescence imaging for tumor diagnosis while markedly suppressing tumor growth under light irradiation with limited systemic toxicity. This work establishes an activation-reported molecular theranostic strategy that integrates tumor diagnosis and multimodal therapy through a shared GSH-triggered mechanism.

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