Ultrasmall radical metal organic cage as cascade antioxidant nanozyme for renal injury.

As substitutes for natural enzymes, nanozymes offer tunable enzyme-like activities and remarkable structural stability, granting them the potential to treat various diseases, including renal ischemia-reperfusion (I/R) injury. However, the majority of developed nanozymes suffer from unclear structures and limited activity profiles, which hinder the study of their structure-activity relationships, catalytic diversity, mass production, and clinical application. Herein, we introduce an atomically precise and ultrasmall cascade nanozyme based on a radical-functionalized metal-organic cage (MOC-R). This nanozyme is synthesized through the coordination of radical ligands with copper ions, resulting in a cuboctahedral structure. The MOC-R exhibits cascade antioxidant activities, mimicking the functions of superoxide dismutase (SOD) and catalase (CAT), owing to the synergism between the external radicals and internal copper clusters. The MOC-R nanozyme demonstrates exceptional radical scavenging and anti-inflammatory properties. It mitigates immune cell infiltration, promotes macrophage polarization towards the M2-like phenotype, reduces inflammatory cytokine secretion, and suppresses excessive autophagy and apoptosis. This study not only presents an atomically precise cascade nanozyme but also highlights its promising therapeutic potential for renal I/R injury.