Dual-functional DNA nanoribbon-templated copper nanoclusters synergistically activate NRF2/HO-1 pathway for synergistic oxidative stress mitigation.

Employing antioxidant nanozymes to eliminate reactive oxygen species (ROS) is a promising strategy for alleviating oxidative stress. However, most current nanozymes struggle to balance catalytic efficacy with biosafety, limiting their clinical applicability. In this study, we introduce a novel platform: DNA nanoribbon-templated copper nanoclusters (DNR/Cu NCs), which harness dual antioxidative mechanisms (direct ROS scavenging and activation of nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) pathway) to synergistically mitigate oxidative stress. Unlike conventional nanozymes that rely on a single mechanism, DNR/Cu NCs exhibit combined superoxide dismutase (SOD)/catalase (CAT)/glutathione peroxidase (GPx), thereby enhancing overall ROS elimination. The biocompatible DNR scaffold facilitates the formation of ultrasmall Cu NCs with high catalytic activity and promotes NRF2 nuclear translocation to transcriptionally upregulate HO-1, amplifying endogenous antioxidant defenses. In both hepatocyte and zebrafish models of oxidative injury, the DNR/Cu NCs effectively suppressed ROS accumulation, suppressed apoptosis, and restored redox balance while mitigating tissue damage in vivo. This study highlights a paradigm-shifting approach in nanozyme design, offering a promising therapeutic avenue for oxidative stress-related diseases.