Exploiting Cancer Vulnerabilities by Blocking of the DHODH and GPX4 Pathways: A Multifunctional Bodipy/PROTAC Nanoplatform for the Efficient Synergistic Ferroptosis Therapy

Abstract Ferroptosis is a form of programmed cell death and plays an important role in many diseases. Dihydroorotate dehydrogenase (DHODH) and glutathione peroxidase 4 (GPX4) play major roles in cell resistance to ferroptosis. Therefore, inactivation of these proteins provides an excellent opportunity for efficient ferroptosis‐based synergistic cancer therapy. In this study, a multifunctional nanoagent (BPN pro ) containing a GPX4 targeting boron dipyrromethene (Bodipy) probe (BP) and a DHODH targeting proteolysis targeting chimera (PROTAC) is reported. BPN pro is prepared using a nanoprecipitation method in the presence of a thermoresponsive liposome, where BP is encapsulated inside and the cathepsin B (CatB)‐cleavable PROTAC peptide (DPCP) is modified on the outer surface. In the presence of near‐infrared (NIR) photoirradiation, BPN pro is melted and BP is released in tumor cells. Subsequently, BP inhibits the activity of GPX4 by covalently bonding with the selenocysteine at the enzyme active site. In addition, DPCP achieves sustained degradation of DHODH upon activation by CatB overexpressed in the tumor. The synergistic deactivation of GPX4 and DHODH induces extensive ferroptosis and subsequent cell death. In vivo and in vitro studies clearly show that the proposed ferroptosis therapy provides excellent antitumor effect.