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Specific therapeutic interventions of hepatic ischemia-reperfusion injury (IRI) to attenuate liver dysfunction or multiple organ failure following liver surgery and transplantation remain a key concern. Here we present an innovative strategy by integrating a platinum nanoantioxidant and nitric oxide synthase (iNOS) into the zeolitic imidazolate framework-8 (ZIF-8)-based hybrid nanoreactor for effective prevention of IRI. Platinum nanoantioxidant could scavenge excessive reactive oxygen species (ROS) at the injury site and meanwhile generate oxygen for subsequent synthesis of nitric oxide (NO) under the catalysis of iNOS. Such cascade reaction successfully achieved dual protection for the liver through ROS clearance and NO regulation, remarkably enabling reduction of oxidative stress, inhibition of macrophage activation and neutrophil recruitment, and ensuing suppression of proinflammatory cytokines. The current work establishes a proof of concept of multifunctional nanotherapeutics against IRI, which may provide a promising intervention solution in clinical use.

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