Injectable, antioxidative, and loaded with exosomes/Liproxstatin-1 hydrogel as a potential treatment for retinal ischemia–reperfusion by inhibiting ferroptosis and apoptosis.

• A ROS-responsive hydrogel hybrid system (EL-Gel) loaded with exosomes and Liproxsrain-1 that has anti-apoptotic-, anti-ferroptosis-, and anti-oxidative stress properties. • The exosomes released by EL-Gel can be taken up by R28 cells and retinal cells and retained for a long time. Liproxsrain-1 was detected in the retina at 7 d and 28 d after intravitreal injections of EL-Gel in mice, proving that EL-Gel achieved a slow and long-lasting release. • EL-Gel has a long-lasting and effective protective effect on the RGC and optic nerve in glaucoma. Retinal ischemia–reperfusion is a major cause of vision loss in a variety of ocular diseases, including glaucoma, age-related macular degeneration, diabetic retinopathy, and central retinal artery occlusion. Previous studies have reported the protective effects of injectable hydrogels in optic nerve injury, but reports of multifunctional hydrogels loaded with drugs and bioactive substances that synergistically promote neuroprotection are rare. Here, we designed an injectable, drug-loaded, and reactive oxygen species responsive multifunctional hydrogel. Upon intravitreal injection into a retinal ischemia–reperfusion injury model in mice, the hydrogel released exosomes and liproxstatin-1 over an extended period exceeding a month, leading to a significant recovery of visual function and reduction of retinal ganglion cell loss. The effect was superior to that of the common drug and exosome combination. The results of this study suggest that this multifunctional hydrogel is expected to advance retinal tissue engineering and provide an innovative strategy for acute neuroprotection in retinal ischemia–reperfusion injury. [ABSTRACT FROM AUTHOR]