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The overproduction of reactive oxygen species (ROS) is thought to be the main cause of RIR injury. A variety of natural products, including quercetin (Que), exhibit potent antioxidant activity. However, the lack of an efficient delivery system for hydrophobic Que and the presence of various intraocular barriers limit the effective retinal delivery of Que in clinical settings. In this study, we encapsulated Que into ROS\u2010responsive mitochondria\u2010targeted liposomes (abbreviated to Que@TPP\u2010ROS\u2010Lips) to achieve the sustained delivery of Que to the retina. The intracellular uptake, lysosome escape ability, and mitochondria targeting ability of Que@TPP\u2010ROS\u2010Lips were evaluated in R28 retinal cells. Treating R28 cells with Que@TPP\u2010ROS\u2010Lips significantly ameliorated the decrease in ATP content, ROS generation, and increase in the release of lactate dehydrogenase in an in vitro oxygen\u2013glucose deprivation (OGD) model of retinal ischemia. In a rat model, the intravitreal injection of Que@TPP\u2010ROS\u2010Lips 24\u2009h after inducing retinal ischemia significantly enhanced retinal electrophysiological recovery and reduced neuroinflammation, oxidative stress, and apoptosis. Que@TPP\u2010ROS\u2010Lips were taken up by retina for at least 14\u2009days after intravitreal administration. Molecular docking and functional biological experiments revealed that Que targets FOXO3A to inhibit oxidative stress and inflammation. Que@TPP\u2010ROS\u2010Lips also partially inhibited the p38 MAPK signaling pathway, which contributes to oxidative stress and inflammation. In conclusion, our new platform for ROS\u2010responsive and mitochondria\u2010targeted drug release shows promise for the treatment of RIR injury and promotes the clinical application of hydrophobic natural products.<\/jats:p>","DOI":"10.1002\/btm2.10460","type":"journal-article","created":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T10:33:54Z","timestamp":1669890834000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Reactive oxygen species\u2010responsive mitochondria\u2010targeted liposomal quercetin attenuates retinal ischemia\u2013reperfusion injury via regulating <scp>SIRT1<\/scp>\/<scp>FOXO3A<\/scp> and p38 <scp>MAPK<\/scp> signaling pathways"],"prefix":"10.1002","volume":"8","author":[{"given":"Laien","family":"Zhao","sequence":"first","affiliation":[{"name":"School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative 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