Abstract

A mitochondrial-targeted ceria nanozyme (TC) delivers ceria to macrophage mitochondria, boosting drug delivery. • TC shows potent antioxidant and anti-inflammatory effects, reducing ROS and pro-inflammatory cytokines. • TC ameliorates pulmonary oxidative stress, attenuates inflammation, and mitigates lung damage in acute lung injury. Acute lung injury (ALI), a severe inflammatory condition of the lungs, aggravates disease progression through the induction of oxidative stress and mitochondrial dysfunction. Considering that mitochondria represent the principal site of reactive oxygen species (ROS) generation, the restoration of mitochondrial homeostasis has emerged as a pivotal therapeutic strategy for ALI intervention. There is a compelling need for pharmacologic agents capable of precise mitochondrial targeting within macrophages. Such agents should facilitate targeted mitochondrial delivery, mitigate ROS and pro-inflammatory cytokine production, and elicit dual antioxidant and anti-inflammatory responses, thereby offering a promising therapeutic avenue for ALI. To address this imperative, we constructed 3-(Carboxypropyl) triphenylphosphonium bromide-modified cerium dioxide nanozymes (TPP-CeO₂-NPs, named as TC), which were specifically designed for specific mitochondrial targeting in macrophages. In vitro assays demonstrated that TC markedly attenuated intracellular ROS levels and inhibited the expression of key inflammatory cytokines. Capitalizing on its favorable biosafety profile, we further established a murine model of acute lung injury. Treatment with TC contributed to substantial mitigation of pulmonary damage, as evidenced by reduced edema and diminished infiltration of inflammatory cells. These findings provide compelling evidence supporting the therapeutic potential of TC in the management of acute lung injury. In this study, we developed mitochondria-targeted modified cerium dioxide (CeO₂-NPs) nanoparticles (named TC) by conjugating hydrothermally synth