IrMn-Cluster-Based Artificial Metalloenzymes with Radiosensitized Systemic Antitumor Responses to Prevent Malignant...

Developing radiosensitizing agents to amplify tumor-eradicating effects on primary, regional recurrence, and distant metastases plays a transformative role in modern cancer care. Here, we report the de novo design of biocatalytic artificial metalloenzymes with an IrMn-cluster-based redox center (IMM) to achieve radiosensitized systemic antitumor responses for preventing malignant tumor metastasis and recurrence. Notably, our findings indicate that Mn-organic ligands substantially enrich the electron density of Ir clusters, thereby optimizing their interaction with oxygen species and markedly enhancing the production of both reactive oxygen species and molecular oxygen. When combined with radiotherapy, the IMM effectively amplifies DNA damage and induces pronounced apoptosis by alleviating intratumoral hypoxia. This shift reprograms the tumor microenvironment, enhancing radiosensitivity and facilitating the infiltration and activation of intratumoral CD8⁺ T cells and dendritic cells. Moreover, when integrated with anti-PD-1 therapy, this coordinated therapeutic regimen elicits potent systemic immune responses and durable antitumor memory, effectively suppressing tumor recurrence and metastasis while markedly improving therapeutic efficacy and long-term survival. We anticipate that this conceptual design could offer a promising and translationally relevant nanomedicine platform for radiotherapies.