Enhancing retinal cells anti-attenuation under oxidative stress by NMN-loaded gelatin nanoparticles via efficiently intracellular delivery

Oxidative stress plays a critical role in retinal degeneration, contributing to cellular apoptosis and senescence in retinal pigment epithelial (RPE) cells and retinal ganglion cells (RGCs). Nicotinamide mononucleotide (NMN), a key precursor of NAD + , has shown potential in protecting against oxidative damage; however, its clinical translation is hindered by poor cellular uptake and rapid degradation. In this study, carrier gelatin nanoparticles (GNPs) were used to encapsulate NMN (NMN-GNPs) to resolve that disadvantage for NMN usage. We investigated the efficacy of nano-formulated NMN to protect cells under H 2 O 2 -induced oxidative stress in human retinal cell models: adult retinal pigment epithelial (ARPE)-19 and human induced pluripotent stem cell (hiPSC)-derived RGCs. Results revealed that both free NMN and NMN-GNPs significantly attenuated H 2 O 2 -induced apoptosis and cellular senescence in ARPE-19 cells. However, free NMN showed a limited effect in hiPSC-RGCs, while NMN-GNPs provided significant cytoprotection under a damaged condition. In addition, cellular uptake assays revealed that free NMN had a limited ability to get into RGCs, which was substantially improved by the nanoparticle-mediated formulation (NMN-GNPs) which enhanced intracellular delivery. These results suggest that nanoformulated NMN exhibited facilitated intracellular delivery and enhanced bioavailability which contributed to oxidative stress resilience in retinal cell types and helped retard senescence in both ARPE-19 and hiPSC-RGC scenarios. These findings support the use of NMN-GNPs as a promising nanotherapeutic approach for clinical translation for oxidative stress-related retinal diseases especially for RGC related damages in the future. • Gelatin, a natural biological macromolecule, was engineered into nanoparticles for NMN delivery. • NMN-loaded gelatin nanoparticles (GNP) showed controlled and restricted release behavior and improved intracellular transport. • The nanoformulation (NMN-GNP) suppressed ROS, apoptosis, and senescence in oxidative-stressed retinal cells. • NMN-GNP uniquely enabled neuroprotection in hiPSC-derived retinal ganglion cells. • This biopolymer-based nanomedicine provides a regenerative therapeutic strategy against retinal degeneration.