Spatiotemporally controlled ferritin-targeting PROTAC nanoplatform for visualized manipulation of endogenous “Iron pool” in pancreatic cancer therapy

Pancreatic cancer is a highly malignant tumor with limited response to current therapies. Ferroptosis, as a novel approach in cancer treatment, holds great promise for addressing tumors resistant to conventional treatments. While the introduction of adequate exogenous iron can trigger ferroptosis and be used for magnetic resonance imaging (MRI), the clinical application prospects are hindered by the use of toxic-dose iron. Here, we develop a ferritin-targeting proteolysis targeting chimeras (PROTAC) nanoplatform that can spatiotemporally mobilize intracellular stores of endogenous "Iron Pool", which is composed of an upconversion nanoparticle core, a photosensitizer, a ferritin-targeting PROTAC (termed dFer) linked with a reactive oxygen species (ROS)-cleavable segment, and a pancreatic cancer-targeting peptide. The activity of dFer is initially dormant but can be turned on by ROS generated from the photosensitizer upon near-infrared photoirradiation. Then the activated dFer recognizes and degrades ferritin by redirecting the ubiquitin-proteasome system, leading to a sustained elevation in intracellular iron levels, which can be dynamically monitored in real-time by MRI <i>in vivo</i>. We demonstrated that this endogenous iron-mediated ferroptosis in combination with photodynamic therapy potently inhibits tumor growth. Furthermore, this process enhances the immunogenicity of tumors, offering hope for tumor immunotherapy. Overall, this study provides a visualized endogenous "Iron Pool" manipulation strategy through a spatiotemporal controllable nanoplatform with robust synergistic treatment effects, potentially offering valuable insights into the development of safe and efficient novel cancer therapies.