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

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.