Nitric oxide-releasing nanoparticles protect human retinal pigment epithelium cells and mice retina from prolonged blue light exposure through antioxidant and vascular enhancement

Abstract

Abstract Nitric oxide (NO) is a short-lived free-radical molecule implicated in the pathophysiology of various eye diseases. The regulatory imbalance of NO, either its overproduction or under-production, is a key factor in oxidative stress-related ocular disorders. Given the increasing concern regarding blue-light-induced oxidative stress leading to retinopathy, we postulate that maintaining consistent NO levels through sustained release could be beneficial. To achieve this, we developed and synthesized nano-NO-releasing systems (NORS), with a hydrodynamic size of approximately 130 nm and a surface charge of -10 mV, respectively. Our findings reveal that blue-light irradiation can trigger NO release from NORS in a light-intensity-dependent manner. Furthermore, NORS can be internalized by retinal pigment epithelial (RPE) cells without exhibiting cytotoxic effects at concentrations up to 100 µM. In RPE cells damaged by blue light, NORS effectively counteracted the upregulation of several antioxidant responses at both the protein and gene levels. These include the Nrf-2/Keap-1 and heme oxygenase-1 (HO-1) protein and the glutathione S-transferase (GST) genes (a1-1, a1-2, a1-5). In the C57BL/6 mice model of blue-light-induced retinopathy, chronic low-intensity blue light exposure (300 Lux, 12 hours/day for 28 days) resulted in photoreceptor dysfunction, vascular leakage, and an increase in mean blood flow rate (MBFR), without affecting the thickness of the retina. However, treatment with NORS mitigated the detrimental effects of blue light on the retina, as evidenced by reduced fluorescence leakages and a reversal of the electroretinographic alterations induced by photoreceptor dysfunction. In conclusion, our data suggested that NORS can effectively enable prolonged NO delivery both in vitro and in vivo. This protective effect appears to be accomplished by restoring normal antioxidant responses and improving vascular homeostasis.