Hyaluronic Acid-PEG-PLGA Nanoparticles Encapsulating Myricetin Attenuate NMDA-Induced Retinal Ganglion Cell Injury Associated with Microglia-Related Neuroinflammatory Responses.

Background: Retinal ganglion cell (RGC) injury caused by excitotoxic stress is an important component of retinal neurodegeneration. Microglia-mediated inflammatory responses can amplify neuronal damage following injury. Myricetin (MY), a natural flavonoid with anti-inflammatory properties, has potential neuroprotective activity but is limited by poor aqueous delivery characteristics. This study aimed to develop a nanoparticle-based delivery system for MY and evaluate its protective effects against NMDA-induced retinal injury. Methods: MY was encapsulated into hyaluronic acid-polyethylene glycol-poly (lactic-co-glycolic acid) nanoparticles (MY-NPs). Nanoparticle characteristics, including particle size, drug loading, encapsulation efficiency, morphology, and in vitro release profile, were evaluated. An NMDA-induced retinal injury model was established in mice, followed by intravitreal administration of MY-NPs. Retinal function, RGC survival, apoptosis, inflammatory responses, and microglial activation were assessed using electroretinography, optomotor testing, immunofluorescence, histological analysis, TUNEL staining, RNA sequencing, and quantitative PCR. The anti-inflammatory effects of MY-NPs were further evaluated in activated BV2 microglia and microglia-conditioned medium-treated R28 cells. Results: MY-NPs showed favorable physicochemical properties, with an average diameter of 67.1 nm, drug loading of approximately 7.4%, and encapsulation efficiency above 80%. The nanoparticles exhibited a biphasic release profile with prolonged myricetin release over 96 h. In NMDA-treated mice, MY-NPs improved retinal function, preserved RGC density, reduced retinal apoptosis, and decreased TNF-α expression. Transcriptomic analysis indicated that NMDA-induced injury was associated with inflammatory pathways, including cytokine-cytokine receptor interaction, JAK-STAT signaling, and TNF signaling, whereas MY-NPs attenuated the expression of inflammatory-related genes. MY-NPs also reduced pro-inflammatory activation markers and inflammatory mediator production in activated BV2 microglia and alleviated apoptosis of R28 cells induced by activated microglial conditioned medium. Conclusion: HA-PEG-PLGA nanoparticles provide an effective delivery platform for myricetin and MY-NPs are associated with protection against NMDA-induced excitotoxic retinal injury. The observed neuroprotective effects were accompanied by reduced microglial activation and inflammatory responses, suggesting that attenuation of microglia-associated inflammation may contribute to RGC preservation. Further validation in chronic glaucoma-relevant models is required to determine the translational potential of this strategy.