Orchestrating apoptosis and ferroptosis through enhanced sonodynamic therapy using amorphous UIO-66-CoO_x

The development of efficient and multifunctional sonosensitizers is crucial for enhancing the efficacy of sonodynamic therapy (SDT). Herein, we have successfully constructed a CoO_x-loaded amorphous metal-organic framework (MOF) UIO-66 (A-UIO-66-CoO_x) sonosensitizer with excellent catalase (CAT)- and glutathione-oxidase (GSH-OXD)-like activities. The A-UIO-66-CoO_x exhibits a 2.6-fold increase in singlet oxygen (¹O₂) generation under ultrasound (US) exposure compared to crystalline UIO-66 sonosensitizer, which is attributed to its superior charge transfer efficiency and consistent oxygen (O₂) supply. Additionally, the A-UIO-66-CoO_x composite reduces the expression of glutathione peroxidase (GPX4) by depleting glutathione (GSH) through Co³⁺ and Co²⁺ valence changes. The high levels of highly cytotoxic ¹O₂ and deactivation of GPX4 can lead to lethal lipid peroxidation, resulting in concurrent apoptosis and ferroptosis. Both in vitro and vivo tumor models comprehensively confirmed the enhanced SDT antitumor effect using A-UIO-66-CoO_x sonosensitizer. Overall, this study emphasizes the possibility of utilizing amorphization engineering to improve the effectiveness of MOFs-based sonosensitizers for combined cancer therapies.