Copper Single-Atom-Based Metal–Organic Framework for Ultrasound-Enhanced Nanocatalytic Therapy

Chemodynamic therapy (CDT) is an emerging therapeutic modality triggered by endogenous substances in the tumor microenvironment (TME) to generate reactive oxygen species. However, the mild acid pH, low H₂O₂ concentration, and overexpressed glutathione can suppress the CDT efficiency. Herein, ultrasound (US)-triggered Cu²⁺-based single-atom nanoenzymes (FA-NH₂-UiO-66-Cu, FNUC) are constructed with the performance of target and glutathione depletion. In the TME, the single-atom Cu sites of FNUC consume glutathione and the FNUC:Cu⁺ generates •OH via peroxidase-like activity. The US-activated FNUC exhibits a fast •OH generation rate, a low Michaelis constant, and a large •OH concentration, indicating the cavitation effect of US promotes the •OH generation. Meanwhile, the tumor target of FNUC is confirmed by NIR-II fluorescence imaging, in which it is modified with IR-1061. Combined with the antitumor performance of FNUC in vitro and in vivo, the novel Cu-based SAzymes can achieve efficient and precise cancer treatment.