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Here, we engineered a ROS\u2010responsive ocular delivery system based on N1\u2010(4\u2010boronobenzyl)\u2010N3\u2010(4\u2010boronophenyl)\u2010N1, N1, N3, N3\u2010tetramethylpropane\u20101,3\u2010diaminium (TSPBA)\/poly(vinyl alcohol) (PVA) hydrogel microspheres (TP hydrogel microspheres) encapsulating 20\u2010deoxyingenol (20\u2010DOI), which enables sustained and ROS\u2010triggered drug release. Under high\u2010glucose conditions in vitro, which were used to model a diabetic microenvironment associated with elevated oxidative stress, TP\/20\u2010DOI microspheres promoted macrophage polarization from the M1 phenotype toward the M2 phenotype. Transcriptomic and metabolic analyses indicated that this shift was driven by enhanced autophagy and concurrent metabolic rewiring from glycolysis to oxidative phosphorylation. In streptozotocin\u2010induced diabetic mice with corneal abrasions, topical TP\/20\u2010DOI microspheres significantly accelerated re\u2010epithelialization and nerve regeneration while attenuating inflammation. The mechanism involved the autophagy\u2010dependent suppression of macrophage M1 polarization, which diminished the levels of macrophage\u2010derived C\u2010X\u2010C motif chemokine ligand 3 (CXCL3)\/CXCL5 and neutrophil infiltration, as evidenced by the reversal of these effects upon pharmacological autophagy inhibition. Our findings establish an \u201cautophagy\u2013metabolism\u2013polarization\u201d axis as the core mechanism through which the microenvironment\u2010responsive TP\/20\u2010DOI microspheres coordinate diabetic corneal repair, providing a blueprint for immunometabolic reprogramming therapies in ROS\u2010driven diabetic complications.<\/jats:p>","DOI":"10.1002\/advs.77232","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T10:47:52Z","timestamp":1787050072000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ROS\u2010Responsive Eye Drop for Controlled Release of 20\u2010Deoxyingenol Improves Diabetic Corneal Healing by Activating Macrophage Autophagy and Metabolic Reprogramming"],"prefix":"10.1002","author":[{"given":"Jiaxin","family":"Wu","sequence":"first","affiliation":[{"name":"International Ocular Surface Research Center Institute of Ophthalmology Key Laboratory for Regenerative 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