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Current first\u2010line therapeutics, vascular endothelial growth factor (VEGF) antagonists, often yield incomplete and suboptimal vision improvement, necessitating the exploration of novel and efficacious therapeutic approaches. Herein, a supramolecular engineering strategy to construct moringin (MOR) loaded \u03b1\u2010cyclodextrin (\u03b1\u2010CD) coated nanoceria (M@CCNP) is constructed, where the hydroxy and newly formed carbonyl groups of \u03b1\u2010CD interact with the nanoceria surface via O\u2500Ce conjunction and the isothiocyanate group of MOR inserts deeply into the \u03b1\u2010CD cavity via host\u2013guest interaction. By exploiting the recycling reactive oxygen species (ROS) scavenging capability of nanoceria and the anti\u2010inflammation properties of MOR, the two\u2010level strike during AMD pathogenesis can be precisely blocked by M@CCNP. Remarkably, excellent therapeutic efficacy to CNV is observed in vivo, achieving over 80% reduction in neovascularization and over 60% reduction in leakage area. In summary, the supramolecular engineered nanoceria provides an efficient approach for amelioration of AMD by blocking the two\u2010level strike, and presents significant potential as an exceptional drug delivery platform, particularly for ROS\u2010related diseases.<\/jats:p>","DOI":"10.1002\/advs.202408436","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T14:11:26Z","timestamp":1736518286000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Supramolecular Engineering of Nanoceria for Management and Amelioration of Age\u2010Related Macular Degeneration via the Two\u2010Level Blocking of Oxidative Stress and Inflammation"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3948-9054","authenticated-orcid":false,"given":"Mingyu","family":"Xu","sequence":"first","affiliation":[{"name":"Eye Center, The Second Affiliated Hospital School of Medicine 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