Radio-Activable Gold-Single-Atom-Based Artificial Enzymes with Cascade Biocatalysis and Enhanced Radiosensitization to Prevent Metastasis and Recurrence in Malignancies

Radiotherapy is a cornerstone of oncological treatment and is frequently used in combination with chemotherapy or immunotherapy. However, its effectiveness is often limited by radioresistance and insufficient activation of systemic antitumor immunity. Overcoming these challenges necessitates the development of innovative radio-activable agents that can enhance therapeutic efficacy and suppress metastasis and recurrence. Here, we present the <i>de novo</i> design of a radio-activable gold-single-atom-based artificial enzyme (Au-RadioSAE) system with superior biocatalysis and radiosensitization to prevent metastatic recurrence. Upon activation by radiotherapy, Au-RadioSAE triggers a rapid increase in intracellular reactive oxygen species, amplifies DNA damage, and initiates potent cell necroptosis. Simultaneously, it remodels the tumor immune microenvironment by enhancing CD8⁺ T cell infiltration, promoting M1 macrophage polarization, and enhancing radioimmunotherapy. In a CT26 murine model, Au-RadioSAE significantly inhibited tumor growth and recurrence. When combined with an anti-PD-1 immune checkpoint inhibitor, it strongly induced immunogenic cell death in nonirradiated tumors, leading to the synergistic suppression of metastatic growth. This innovative design offers a promising strategy for developing radio-activable artificial enzymes that synergize radiotherapy and immunotherapy, particularly in preventing metastasis and recurrence in advanced malignancies.