A Biomimetic Nanoagonist for Synergistic Photodynamic/Ferroptosis/Disulfidptosis Therapy via Coinhibition of Glucose Metabolism and the SLC7A11/GSH/GPX4 Axis

Photodynamic therapy (PDT) faces significant challenges in clinical applications, including tumor hypoxia, the poor water solubility of photosensitizers, and insufficient targeting specificity. To address these limitations, we developed a biomimetic nanoagonist, 4T1@MFCB, by coloading a near-infrared photosensitizer (CyI) and a GLUT1 inhibitor (BAY-876) into a manganese/iron bimetallic metal–organic framework (MOF), followed by coating with the homologous 4T1 cell membrane. The manganese component catalyzes the decomposition of endogenous H2O2 to generate oxygen, alleviating tumor hypoxia and enhancing PDT efficacy, while the iron component promotes ferroptosis via the Fenton reaction. Meanwhile, BAY-876 inhibits glucose uptake, disrupting NADPH production and the cystine-to-cysteine reduction process, which leads to cystine accumulation and glutathione (GSH) depletion. These effects collectively suppress the Solute Carrier Family 7 Member 11(SLC7A11)/glutathione (GSH)/glutathione peroxidase 4 (GPX4) antioxidant axis, thereby triggering disulfidptosis. Under near-infrared irradiation, CyI mediates effective photodynamic and photothermal therapy (PTT). Both in vitro and in vivo studies demonstrate that 4T1@MFCB enables synergistic PDT/ferroptosis/disulfidptosis therapy, significantly inhibiting tumor growth without obvious systemic toxicity. This work highlights a multimodal treatment strategy that integrates metabolic intervention with nanocatalytic therapy, providing a promising approach for the precision treatment of hypoxic and therapy-resistant tumors.