Abstract

It is well established that 7,8-dihydroxyflavone (DHF) exerts protective effects against ischemia-reperfusion injury (IRI)-induced acute kidney injury (AKI). However, its clinical translation has been largely restricted due to rapid metabolism and insufficient bioavailability. To address this challenge, we designed a multifunctional hybrid nanoplatform, DHF@ZIF-8, which integrates the therapeutic advantages of both drug molecules and metal-organic frameworks. Unlike conventional delivery systems, DHF@ZIF-8 not only enables sustained and targeted release of DHF but also exhibits intrinsic enzyme-mimicking activity, thereby providing dual protection against oxidative stress through controlled pharmacological action and catalytic antioxidation. In vitro studies on hypoxia/reoxygenation induced HK-2 cells demonstrated that DHF@ZIF-8 significantly suppressed ROS-induced apoptotic signalling more effectively than DHF or ZIF-8 alone. More importantly, in vivo experiments further confirmed the superior biocompatibility, renal enrichment, and therapeutic efficacy of this hybrid nanozyme. Collectively, we for the first time identified DHF@ZIF-8 as a drug-nanozyme delivery system with excellent biosafety, offering an innovative and sustainable strategy for combating ROS-driven AKI.