Glutathione-Depleting and Reactive Oxygen Species-Amplifying Upconversion Nanoplatform for Synergistic Ferroptosis

The overexpression of glutathione (GSH) in tumor cells neutralizes reactive oxygen species (ROS), thereby limiting oxidative stress-induced cell death. In this study, we develop a tumor-responsive upconversion nanoparticle (UCNPs)-based nanoplatform, UCNPs@mMnO 2 –Hypricin (UM-H), designed to deplete intracellular GSH and potentiate ROS-mediated antitumor therapy. The MnO 2 shell selectively degrades in the presence of GSH, releasing Mn 2+ ions, restoring UCNP luminescence, and serving as an indicator of GSH depletion. The released Mn 2+ forms complexes with hypericin, enhancing ROS generation. Furthermore, Mn 2+ catalyzes the Fenton reaction, generating hydroxyl radicals (·OH) to amplify oxidative damage, resulting in significant tumor suppression with minimal toxicity.