CDT Prodrug Therapy With Cascade‐Activated PROTAC Delivery Platform for Mutually Reinforced Ferroptosis and Apoptosis‐Based Therapy

Abstract Proteolysis‐targeting chimeras (PROTACs) have emerged as a promising strategy for targeting traditionally “undruggable” proteins in cancer therapy. However, their clinical translation is hindered by challenges such as poor water solubility and off‐target protein degradation. Herein, a hydroxyl radical‐activatable PROTAC prodrug is prepared and assembled them with ultrasmall iron nanoparticles (USINPs) in tumor acidity responsive polymersome for nanoenzyme boosted and cascade activation of PROTAC. The assembly can target tumor and specifically disintegrated in tumor microenvironment. Recovered USINPs elevated ROS level, not only can induce ferroptosis but also activate PROTAC prodrug. Meanwhile, the PROTAC activation leads to the degradation of the target protein bromodomain‐containing protein 4 (BRD4) to trigger apoptosis, while simultaneously inhibit the expression of glutathione peroxidase 4 (GPX4) to amplify ferroptosis. This study achieves synergistic tumor suppression through the mutually reinforcing mechanisms of ferroptosis and apoptosis. The design for tumor‐triggered cascade activation of PROTAC prodrug provides a new way to precisely degrade tumor‐targeted protein for cooperative anticancer therapy.