Heterometallic organic cages as cascade antioxidant nanozymes to alleviate renal ischemia-reperfusion injury.

[Display omitted] • Heterometallic organic cages with tunable metal ratios were constructed. • The heterometallic organic cages exhibited remarkable cascade antioxidant nanozyme activities. • The synergistically enhanced enzyme activity was elucidated through experiments and theoretical calculations. • The cascade nanozyme can effectively alleviate renal ischemia–reperfusion injury. The regulation of reactive oxygen species (ROS) by antioxidant enzymes plays a crucial role in managing tissue ischemia–reperfusion (I/R) injury. However, the imprecise structures of most developed nanozymes pose significant challenges for their structure–activity interpretation and clinical translation. Additionally, the monotonous enzyme-like activity exhibited by most nanozymes also restricts their efficacy. In this study, we have developed well-defined cascade nanozymes based on metal organic cages (MOCs) to effectively eliminate excessive ROS in the context of renal I/R injury. By integrating nickel and cobalt within the MOC, we obtained heterometallic organic cage (HMOC) nanozymes with adjustable metal ratios. The incorporation of these two metals into a single MOC nanozyme not only expands its catalytic activity but also enables it to facilitate complex antioxidant reactions more effectively than traditional multi-step processes. The performance of HMOC cascade nanozymes, which mimic the cascade activities of superoxide dismutase (SOD) and catalase (CAT), in converting superoxide anion radicals (O 2 –) into oxygen and water is synergistically enhanced by the heterometallic interactions within a single metal cluster in the HMOC structure. Through optimization of the metal ratio within HMOC-2, both in vitro and in vivo experiments demonstrate that its ROS-scavenging capacity surpasses that of other groups significantly, thereby effectively alleviating renal I/R injury. This study not only presents well-defined enzyme-like cascade systems but also highlights their promising therapeutic potential for treating renal I/R injury. [ABSTRACT FROM AUTHOR]