Dual-radical generating FePEIDN nanocomposite for tumor therapy: Sulfite radical persistence meets Fenton catalysis

This work reports on a nanocomposite FePEIDN, which can specifically respond to the tumor microenvironment (TME) to generate sulfite radicals (·SO 3 − ) with long half-life for effective tumor therapy. FePEIDN could respond to GSH overexpressed within the tumor to generate SO 3 2− . Meanwhile, FePEIDN is capable of initiating the Fenton reaction and generating peroxidase-like Fe (III) species that catalyze SO 3 2− to · SO 3 − to triggering cell death. • The material responds to tumor environment to generate sulfite radicals. • Dual sulfite/hydroxyl radicals synergy achieves tumor suppression in vivo . • This study offers insights for tumor therapies based on biomolecule interactions. Sulfite radicals ( · SO 3 - ) are sulfur-centered reactive species with relatively strong oxidizing and nucleophilic properties, showing great promise for tumor therapy by interacting with numerous biomolecules. However, the massive in situ generation of · SO 3 - in tumor cells poses a significant challenge. Therefore, it is of great importance to explore novel strategies that facilitate the efficient in situ generation of · SO 3 - . Here, we engineered a nanocomposite FePEIDN, capable of specifically responding to the tumor microenvironment (TME) to generate · SO 3 - with long half-life for efficient tumor treatment. In this nano-system, amorphous iron (amorphous Fe 0 ) nanoparticles were modified with polyetherimide (PEI), followed by covalent conjugation of 2,4-dinitrobenzenesulfonyl (DN) moiety onto their surface to obtain the desired FePEIDN. The FePEIDN responded to high concentrations of glutathione (GSH) in the TME to form sulfite (SO 3 2- ). Simultaneously, FePEIDN could release Fe 2+ , initiating the Fenton reaction to convert the overproduced H 2 O 2 into hydroxyl radicals ( · OH) and generating peroxidase-like Fe (III) species that catalyze SO 3 2- to · SO 3 - . Both in vitro and in vivo findings revealed that FePEIDN exhibited a satisfactory therapeutic effect on tumors. This work not only sheds light on an avenue for combating cancer but also provides promising insights into the development of innovative anti-cancer drugs.