Synergistic cerium oxide nanozymes: targeting DNA damage and alleviating tumor hypoxia for improved NSCLC radiotherapy efficiency

Radiotherapy (RT) is one of the important treatment modalities for non-small cell lung cancer (NSCLC). However, the maximum radiation dose that NSCLC patient can receive varies little. Therefore, the exploitation of novel RT sensitization approaches is a critical need for the clinical treatment. RT resistance in NSCLC is linked to tumor microenvironment (TME) hypoxia, cell cycle arrest and associated genetic alterations. Here, we designed a novel method for targeted delivery of quercetin (QT) and CeO 2 to enhance RT sensitivity. We loaded QT into CeO 2 @ZIF-8-HA nanoparticles to prevent its degradation in the circulatory system and successfully delivered QT and CeO 2 targeted to NSCLC tumors. Under the protection and targeted delivery of Zeolitic Imidazolate Framework-8 (ZIF-8), the nanocomplexes exhibited excellent catalytic mimetic activity in decomposing H 2 O 2 into O 2 , thus significantly reversing the hypoxia of TME, while the radiosensitizer QT caused DNA damage directly after RT. In a subcutaneous tumor model, CeO 2 @ZIF-8-HA overcame radiation resistance and enhanced therapeutic efficacy. This multiple sensitization strategy combining delivery of QT and CeO 2 @ZIF-8-HA nanozymes opens a promising approach for RT of NSCLC.