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A nanozyme-based drug delivery system to amplify ferroptosis via MET inhibition and photodynamic therapy

Mengran Xu,Fuxuan Lai,Hu Liu,Delin Hu,Yexiang Sun,Fenfen Li,Min Sun,Na Lv,Bensheng Qiu,Yueyin Pan,Yi Hu

Ferroptosis, a relatively recently discovered form of programmed cell death, has garnered considerable attention in the field of cancer drug discovery. However, effectively inducing ferroptosis at tumor sites and maximizing its therapeutic efficacy remains a formidable challenge. In the present study, we constructed the MIL-53@cMBP@ST/Ce6 (MMSC) nanocomplex to enhance the therapeutic efficacy of a ferroptosis-inducing drug. This was accomplished by modifying the cMBP peptide and encapsulating a small molecular ferroptosis inducer, sorafenib tosylate (ST), along with a photosensitizer, Chlorin e6 (Ce6), within the iron-based nanozyme MIL-53, which exhibits multiple enzyme-like activities. The glutathione (GSH) oxidase-like activity of MIL-53 depletes GSH, which is known to contribute to ferroptosis resistance in tumors. The catalase-like activity of MIL-53 catalyzes the decomposition of H 2 O 2 within the tumor, yielding oxygen to enhance the effect of photodynamic therapy. Concurrently, the photodynamic effect of MMSC generates singlet oxygen ( 1 O 2 ), further amplifying ferroptosis. Additionally, modification of the cMBP peptide enabled MMSC to attenuate the MET pathway in MET-overexpressing tumors, thereby decreasing the antioxidant capacity of these cells to promote ferroptosis. Notably, transcriptomic analysis revealed that PDT enhances the ferroptosis pathway and modulates the expression of ferroptosis-related genes and MET signaling pathways-related genes, while Western Blot results confirmed the inhibition of GPX4 protein, a critical regulator of ferroptosis. In vivo, MMSC demonstrated a tumor-specific accumulation effect, as evidenced by fluorescence imaging, and significantly inhibited tumor growth by alleviating the hypoxic tumor microenvironment and enhancing ferroptosis at the tumor site. This study presents a novel strategy for the mechanistic investigation of augmented ferroptosis in tumor therapy.