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

<b>Rationale:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusions:</b> This study not only presents an atomically precise cascade nanozyme but also highlights its promising therapeutic potential for renal I/R injury.