Metallosalphen-Covalent Organic Framework-Based Semiconducting Artificial Enzymes with Radio-Activable Antitumor Immunity for Suppressing Tumor Metastasis and Recurrence

Reactive oxygen species (ROS)-catalytic therapies have gained increasing popularity in preventing tumor metastasis and recurrence, yet their efficiency is often compromised by limited systemic immune activation. Herein, we report the <i>de novo</i> design of Ru-coordinated bis-Schiff base salphen-covalent organic frameworks (SCOF-Ru) to serve as semiconducting artificial enzymes with radio-activable ROS-catalytic efficiency and antitumor immunity for suppressing tumor metastasis and recurrence. Experimental and theoretical results demonstrate that the semiconducting SCOF-Ru displays large π-conjugation, efficient electron transfer, strong electron-hole separation, and unique Ru₂-N₄O₂ catalytic centers, enabling the most superior ROS production capability under low-dose X-ray irradiation. Rather than relying on high-Z elements, semiconducting SCOF-Ru with optimized band structures endows Ru sites with high radiosensitization effects. Our findings have disclosed that the SCOF-Ru can not only effectively inhibit DNA repair but also trigger robust apoptosis through the downregulation of calcium signaling pathways. Correspondingly, the therapeutic superiority and recurrence inhibition efficacies of SCOF-Ru have been validated in different tumor models, especially radiotherapy-resistant patient-derived xenograft models. Combined with immune checkpoint blockade, radio-activable SCOF-Ru shows great potential to robustly inhibit the growth of distant tumors. We believe the innovative design of ROS-catalytic and radio-activable artificial enzymes will enable a promising avenue for treating malignant tumors.