Targeted ROS-responsive micelle-gel system for enhanced bioavailability and sustained delivery of dexamethasone in corneal neovascularization therapy.

Corneal neovascularization (CoNV) remains difficult to treat due to limited ocular drug retention, insufficient targeting, and rapid clearance. Herein, a reactive oxygen species (ROS)-responsive and integrin-targeted micelle-gel composite delivery system was developed to enhance ocular bioavailability and therapeutic efficacy. Methoxy poly(ethylene glycol)-poly(propylene sulfide) (mPEG-PPS) was synthesized and co-assembled with cRGD-PEG-PLGA to form dexamethasone-loaded hybrid micelles (cRGD-DPPMs) with a mean particle size of 144.9 ± 2.95 nm, a drug loading of 7.62 ± 0.16%, an encapsulation efficiency of 89.74 ± 0.37%. The micelles were further incorporated into a hypotonic Pluronic F127 gel (12%, 51.3 ± 5.9 mOsm·kg⁻1) to obtain a ROS-responsive micelle-gel system (cRGD-DPPMs/Gel) with enhanced ocular adhesion. In vitro release studies demonstrated ROS-triggered drug release, reaching 83.17% within 72 h under 5% H2O2, while maintaining sustained release under physiological conditions. Cellular uptake by αvβ3-overexpressing HUVECs was increased by approximately 2.8-fold following cRGD modification. In a rat alkali burn-induced CoNV model, cRGD-DPPMs/Gel significantly reduced the neovascularized area to 19.04% after 14 days, compared with 47.62% in the untreated model group, while markedly suppressing inflammatory cytokines and VEGF expression without elevating intraocular pressure. This formulation represents a pharmaceutically rational strategy for sustained and targeted ocular therapy of CoNV.