415 Designing nanoparticle therapies for age-related macular degeneration

Objectives/Goals: Our objective in this study was to develop a nanoparticle-based RNA delivery system that reprograms Müller glia toward neuronal fates in human relevant models, enabling localized and transient regeneration without viral vectors. Methods/Study Population: - Results/Anticipated Results: Fabricated nanoparticles encapsulating RNA cargoes were ~110–150 nm in size with polydispersity indices of ~0.2–0.3 and encapsulation efficiencies >95%. Nanoparticles successfully delivered GFP mRNA in both organoid and retinal explant models, showing significant expression of fluorescent reporters in both live cell imaging and in slides prepared using immunohistochemistry. We anticipate that our delivery system will lead to transcription factor expression after delivery of corresponding RNAs with evidence of proliferation and neuronal marker upregulation. We also hypothesize that this approach will enhance neurogenesis in retinal organoids and explants, potentially establishing a platform for non-viral retinal regeneration. Discussion/Significance of Impact: This work demonstrates a clinically translatable, virus-free strategy for retinal repair through targeted RNA delivery. By enabling transient expression of neurogenic factors, nanoparticle-mediated reprogramming presents a scalable and adaptable approach for restoring vision in degenerative retinal diseases.