Oxygen‐Evolving Radiotherapy‐Radiodynamic Therapy Synergized with NO Gas Therapy by Cerium‐Based Rare‐Earth Metal‐Porphyrin Framework

Abstract The efficacy of traditional radiotherapy (RT) has been severely limited by its significant side effects, as well as tumor hypoxia. Here, the nanoscale cerium (Ce)‐based metaloxo clusters (Ce(IV) 6 )‐porphyrin (meso‐tetra (4‐carboxyphenyl) porphyrin, TCPP) framework loaded with L‐arginine (LA) (denoted as LA@Ce(IV) 6 ‐TCPP) is developed to serve as a multifarious radio enhancer to heighten X‐ray absorption and energy transfer accompanied by O 2 /NO generation for hypoxia‐improved RT‐radiodynamic therapy (RDT) and gas therapy. Within tumor cells, LA@Ce(IV) 6 ‐TCPP will first react with endogenous H 2 O 2 and inducible NO synthase (iNOS) to produce O 2 and NO to respectively increase the oxygen supply and reduce oxygen consumption, thus alleviating tumor hypoxia. Then upon X‐ray irradiation, LA@Ce(IV) 6 ‐TCPP can significantly enhance hydroxyl radical (•OH) generation from Ce(IV) 6 metaloxo clusters for RT and synchronously facilitate singlet oxygen ( 1 O 2 ) generation from adjacently‐coordinated TCPP for RDT. Moreover, both the •OH and 1 O 2 can further react with NO to generate more toxic peroxynitrite anions (ONOO − ) to inhibit tumor growth for gas therapy. Benefitting from the alleviation of tumor hypoxia and intensified RT‐RDT synergized with gas therapy, LA@Ce(IV) 6 ‐TCPP elicited superior anticancer outcomes. This work provides an effective RT strategy by using low doses of X‐rays to intensify tumor suppression yet reduce systemic toxicity.