Boosting ferroptosis by intervention of redox balance and synergetic with photothermal/photodynamic therapy for suppression of pancreatic cancer

Metal-doped iron oxide nanoparticles have attracted increasing attention for their Fenton reaction ability, which converts H 2 O 2 to cytotoxic reactive oxygen species (ROS) and is recently utilized as ferroptosis activator in pancreatic cancer therapy. However, low intracellular H 2 O 2 level hinders ferroptosis effect and leads to unsatisfactory efficacy. Herein, a transferrin coated and tumor homing peptide decorated bimetallic magnetic nanoparticles copper-doped iron oxide nanosystems embedded with photothermal agent IR820 and iron ions (denoted as PCTIFL) is constructed for synergistic treatment for pancreatic cancer by combining ferroptosis and photothermal/photodynamic therapy (PTT/PDT) under 808 nm laser irradiation. Benefiting from the homologous targeting property of LyP-1, the nanosystems can be precisely delivered and gradually accumulate at tumor site. For the synergistic therapy, IR820 generates ROS via photodynamic effect and enables cancer cell temperature elevation via PTT effect upon 808 nm laser irradiation on the one hand and metal ions such as Fe 2+ , Fe 3+ and Cu 2+ catalyze H 2 O 2 into ROS and finally triggered ferroptosis on the other hand. Moreover, PCTIFL nanosystems can be applied in pancreatic cancer diagnosis for their MRI/NIR dual imaging function. Overall, this work not only presents a promising strategy for augmenting the ferroptosis induced by iron oxide, but also a fantastic paradigm for pancreatic cancer diagnosis and synergistic therapy.