Engineered calcium carbonate-modiated SAzymes with Mn-based single-atom sites for ultrasound-enhanced nanocatalytic...

The construction of highly effective therapeutic nano-systems will be of great interest in the investigation of cancer treatment; however, developing such the platforms face significant challenges originated from the strict tumor microenvironment (TME). In this study, the engineered carbonate-mediated SAzyme based on UiO-66-NH₂ with Mn-based single-atom sites and calcium carbonate (CaCO₃@Mn-UiO-66-NH₂, CUM) is successfully developed for dual imaging-guided ultrasound-enhanced nano-catalytic therapy. The designed SAzyme with uniform structure and morphology exhibit good stability and suitable particles sizes. The Mn based single-atoms coordinated in the CUM show excellent peroxidase (POD)-like activity to generate high toxic hydroxyl radical (∙OH) in the TME, and its reactive oxygen species (ROS)-based therapeutic effect can be promoted by the cavitation effect generated from ultrasound (US) irradiation. Owing to the pH-responsive property of CUM in the acidic TME, the coated calcium carbonate-based shell is degraded and then released high concentration of Ca²⁺ ions to induce calcium-mediated cell death. The in vitro and in vivo experiments also confirm a significant increase in apoptosis following CUM intervention, thereby further enhancing the anti-tumor effect upon exposure to US irradiation. The genomic analysis of cancer cells following CUM treatment further identified key genes and associated pathways, which utilize the approach to explore the therapeutic mechanism of the SAzyme. Combined with the synergistic anti-tumor performance of US-activated CUM, this SAzyme provides potential to more effectively inhibit both the initiation and progression of cancer.