Boosting Enzyme-like Activities via Atomization of Cerium for Tumor Microenvironment-Responsive Cascade Therapy

Nanozyme catalytic therapeutic efficacy is limited by the finite enzyme activity and specificity. In this work, nitrogen-doped carbon loaded with a cerium single-atom nanozyme (Ce SAs@NC) is synthesized, exhibiting tumor specificity and excellent multiple enzyme-like activities. Compared with nitrogen-doped carbon loaded with CeO₂ nanoparticles, Ce SAs@NC shows excellent peroxidase-like and catalase-like activity. Ce SAs@NC can convert intracellular hydrogen peroxide into cytotoxic hydroxyl radical and O₂, which can be further transferred to superoxide radicals. Cascade enzyme reactions not only alleviate the hypoxic microenvironment of tumors but also induce lipid peroxidation and apoptosis or necrosis of tumor cells. The mild photothermal action will enhance the enzyme-like activities of Ce SAs@NC rather than induce the production of heat shock proteins to protect tumor cells. In addition, Ce SAs@NC can regulate the immune environment, stimulate M1 macrophages to trigger immune responses, and inhibit tumor proliferation. Thanks to the combination of the size effect of the single atoms, photothermal influence, multiple enzyme-like activities, and immunological effect, the Ce SAs@NC platform appears to have tumor specificity, less toxic side effects, and a high curative effect both in vitro and in vivo.