BSA-assisted synthesis of nanoreactors with dual pH and glutathione responses for ferroptosis and photodynamic synergistic therapy of colorectal cancer

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Colorectal cancer (CRC) is the third most common cancer in global incidence and second most common cancer in global mortality rates, accounting for 10% of all cancer cases and 9.4% of all cancer-related deaths. CRC is a heterogeneous disease, mostly comprising sporadic tumors. Approximately 19%–28% of patients have postoperative metastasis. In this study, we report an epigallocatechin gallate (EGCG)-based metal polyphenol network (MPN) with CD44 targeting, glutathione (GSH) sensitivity and pH response for the codelivery of the photosensitizers chlorin e6 (Ce6) and Fe3+. Photodynamic therapy (PDT) has become a potential clinical treatment method because of its noninvasive nature, low toxicity and spatiotemporally controlled treatment capability. Ferroptosis is a nonapoptotic cell death caused by peroxidative modification of phospholipid membranes via iron-dependent mechanisms. We unified ferroptosis and PDT into a nanoreactor (BSA-Ce6@MPN, BCM) to treat CRC. In vitro analysis showed that laser-irradiated BCM increased the cellular reactive oxygen species (ROS) and lipid peroxide (LPO) contents and decreased the expression levels of GSH and glutathione peroxidase 4 (GPX4). BCM-mediated ferroptosis and PDT synergistic therapy were significantly effective in the CT26 tumor-bearing mouse model, demonstrating the efficacy of the combination therapy. These results suggest that the nanoreactor for the synergistic treatment of ferroptosis and PDT holds great promise for clinical translation.