Biomaterials. 2026 Jul 3;335:124417. doi: 10.1016/j.biomaterials.2026.124417. Online ahead of print.
ABSTRACT
Reactive oxygen species (ROS)-catalytic artificial enzymes have emerged as a promising way to combat malignant tumors, yet their efficacy remains constrained by tumor hypoxia, oxygen dependence, and robust antioxidant defenses. Herein, we report the de novo design of a bioinspired manganese@gold cluster-coordinated covalent organic frameworks-based artificial metalloenzymes (AuC@SCOF-Mn) with efficient cascade biocatalysis and amplified systemic stimulation to combat malignant tumor metastasis. Experimental and theoretical results demonstrate that the AuC@SCOF-Mn heterojunction architecture accelerates electron transfer and drives oxygen-independent type I photoreactions under low-dose light irradiation, which confer dual-enzyme-like activities to catalyze glucose-to-H2O2-to-ROS conversion and deplete intracellular glutathione. The multiple functionalities not only disrupt redox homeostasis to amplify ROS accumulation but also elicit potent tumoricidal effects through mitochondrial dysfunction and DNA damage. Beyond direct cytotoxicity, AuC-SCOF-Mn effectively reprograms the tumor microenvironment by enhancing cytokine-cytokine receptor interactions, thereby promoting dendritic cell antigen presentation, CD8+T cell activation, and NK cell infiltration. Correspondingly, AuC@SCOF-Mn demonstrates potent tumor suppression and long-term inhibition of tumor recurrence in vivo. When combined with checkpoint therapy, it further amplifies systemic antitumor responses and inhibits malignant tumor lung metastasis. We believe the innovative design of ROS-catalytic, photo-activable artificial enzymes will open a promising avenue for treating malignancies.
PMID:42402240 | DOI:10.1016/j.biomaterials.2026.124417