Pore-enhanced reactive oxygen species generation by using covalent organic frameworks for improving sonodynamic therapy of cancer

Covalent organic frameworks (COFs) have generated interest as promising tools for reactive oxygen species (ROS) -mediated therapy owing to designable structures and diversified modification sites. However, the ordered porous structure of COFs and their multiple catalytic sites on the enhancement of ROS-mediated therapy of cancers have attached little attention. Here, we synthesized a nanosonosensitizer named FeTPD@GOx, consisting of the ferriporphyrin-based COF (Fe-COF) loaded with glucose oxidase (GOx) for pore-enhanced ROS-mediated therapy in which GOx catalyzed glucose to H2O2 while Fe3+/Fe2+ cycle catalyzed H2O2 to O-2 and <middle dot>OH. The H2O2/O-2 self-supply cycle inside the pores of COFs enhanced the generation of abundant ROS in situ upon ultrasound (US) irradiation. The mechanism examination revealed that the opening pore channels of COFs not only could catch O-2 with the rapid exchange for O-2 and O-1(2), but also provided more accessible Fenton reaction sites to iron ions for more <middle dot>OH generation, enhancing the efficacy of sonodynamic therapy (SDT) and chemodynamic therapy (CDT). In vivo antitumor evaluation revealed that FeTPD@GOx can not only inhibit the growth of the proximal tumor effectively but also display superior antitumor efficiency to the distant tumor upon US irradiation. Our work, which utilizes the porous structure, multiple catalytic sites, and GOx loading of COFs to hold O-2, thereby promoting gas exchange, realizing sequential catalytic reactions, amplifying ROS generation, and enhancing synergistic effect of SDT and CDT for ROS-mediated therapeutic efficacy, offers prospects for applications of COFs in biomedical fields.