ROS‐Responsive Eye Drop for Controlled Release of 20‐Deoxyingenol Improves Diabetic Corneal Healing by Activating Macrophage Autophagy and Metabolic Reprogramming

Impaired corneal wound healing in diabetes remains a major clinical challenge, driven by defective autophagy, metabolic dysregulation, and sustained inflammation within a high-reactive oxygen species (ROS) microenvironment. Here, we engineered a ROS-responsive ocular delivery system based on N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1, N1, N3, N3-tetramethylpropane-1,3-diaminium (TSPBA)/poly(vinyl alcohol) (PVA) hydrogel microspheres (TP hydrogel microspheres) encapsulating 20-deoxyingenol (20-DOI), which enables sustained and ROS-triggered drug release. Under high-glucose conditions in vitro, which were used to model a diabetic microenvironment associated with elevated oxidative stress, TP/20-DOI 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-induced diabetic mice with corneal abrasions, topical TP/20-DOI microspheres significantly accelerated re-epithelialization and nerve regeneration while attenuating inflammation. The mechanism involved the autophagy-dependent suppression of macrophage M1 polarization, which diminished the levels of macrophage-derived C-X-C 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 "autophagy-metabolism-polarization" axis as the core mechanism through which the microenvironment-responsive TP/20-DOI microspheres coordinate diabetic corneal repair, providing a blueprint for immunometabolic reprogramming therapies in ROS-driven diabetic complications.