Covalent organic framework-based nanozyme for cascade-amplified synergistic cancer therapy

Due to the limited concentration of hydrogen peroxide (H2O2) in the tumor microenvironment, peroxidase (POD)-mimicking nanozyme-mediated catalytic therapy usually cannot completely eliminate tumor issues. In this study, we report an H2O2-responsive nanozyme constructed by loading 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) into POD-like Fe-porphyrin covalent organic frameworks (COFs) (Fe-DhaTph). The resulting ABTS@Fe-DhaTph can function as a multifunctional therapeutic nanoagent for combination therapy of catalytic therapy, photothermal therapy (PTT), and photodynamic therapy (PDT). In the tumor microenvironment, ABTS@Fe-DhaTph can catalyze the decomposition of endogenous H2O2 to produce highly cytotoxic hydroxyl radicals (.OH) for in situ tumor catalytic therapy. Meanwhile, the loaded ABTS is oxidized by H2O2 with the assistance of ABTS@Fe-DhaTph, and the resulting oxABTS, with strong near-infrared absorbance, can enable the H2O2-dependent PTT. Besides Fe-DhaTph-induced PDT, the generated oxABTS with glutathione (GSH)-depletion ability can synergistically enhance the generation of reactive oxygen species, thereby improving catalytic therapy and PDT. To the best of our knowledge, ABTS@Fe-DhaTph is the first COF-based nanozyme to serve as a cascade-amplified synergistic therapeutic nanoagent for cancer treatment.