PROTAC-Loaded Nanoparticles Induce a "ROS Storm" through Targeted Degradation of GPX4 in Combination with a Mild Photothermal/Fenton-like Reaction for the Treatment of Triple-Negative Breast Cancer.

Proteolysis-targeting chimeras (PROTACs) are a promising therapeutic approach for degrading disease-causing proteins. However, they often encounter limitations in in vivo applications due to poor solubility, low cellular permeability, unfavorable pharmacokinetics, and more. To address these challenges, we developed a multifunctional "onion-like" nanoplatform, PB@SiO2@MnO2@dGPX4/PVP (PMDP), which delivers a glutathione peroxidase 4 (GPX4) PROTAC degrader, dGPX4, to induce ferroptosis in triple-negative breast cancer cells. PMDP consists of Prussian blue (PB) nanoparticles that are coated with a protective SiO2 layer and an MnO2 shell. The nanoparticles are encapsulated with polyvinylpyrrolidone after dGPX4 adsorbs onto the surface. The resulting PMDP enhances tumor enrichment and cellular uptake of dGPX4. It also depletes glutathione and catalyzes Fenton-like reactions in cancer cells, generating reactive oxygen species (ROS). PB's near-infrared (NIR) photothermal capability simultaneously facilitates this reaction and enables mild photothermal therapy. Concurrently, dGPX4 effectively degrades the key anti-ferroptosis protein GPX4, thereby disrupting the cellular antioxidant defense system. Studies demonstrate that PMDP induces a "ROS storm", lipid peroxidation, and mitochondrial damage, triggering efficient ferroptosis and significantly inhibiting tumor growth in TNBC models. This research shows the potential to integrate targeted protein degradation with multiple nanomedicine technologies, offering a promising combination strategy for cancer therapy.