Targeted GPX4 Degradation Mediated by Hypoxia‐Overcoming Nano‐PDTACs for Synergistic Ferroptosis–Immunotherapy

For triple-negative breast cancer (TNBC), ferroptosis is a promising therapeutic strategy, with photodynamic therapy (PDT) being an effective method to induce it. However, PDT-induced ferroptosis has limitations such as poor tumor targeting, unclear target specificity, and hypoxia. Thus, we developed a novel nano-photodegradation-targeting chimera (Nano-PDTAC) that achieves efficient ferroptosis in TNBC cells. The Nano-PDTAC (PCN@Pt-TR) is constructed by attaching a GPX4-targeting peptide (T) and a tumor-targeting peptide (R) to platinum nanozyme-modified iron-porphyrin frameworks (PCN@Pt). PCN@Pt-TR enhances tumor targeting by binding to the αvβ3 integrin receptor on tumor cell surfaces, and it has potential for magnetic resonance imaging (MRI)-guided therapy. Once inside tumor cells, PCN@Pt-TR efficiently induces ferroptosis by targeting and degrading the GPX4 protein. Crucially, the O₂ produced by the Pt nanozyme continuously replenished, sustaining the degradation. Additionally, tumor cells undergoing ferroptosis mediated by Nano-PDTAC can induce immunogenic cell death (ICD), and enhance the effectiveness of immune checkpoint blockade. Thus, this is a valuable approach for inducing ferroptosis based on GPX4-targeted Nano-PDTAC, which can overcome the many issues associated with traditional photosensitizers in ferroptosis and may advance the application of ferroptosis in tumor immunotherapy.