Alpinetin Nanoparticles Alleviate Optic Nerve Injury Induced by Acute Glaucoma via LRP1‐PPARγ Mediated Regulation of Microglial Lipid Metabolism

Abstract Glaucoma is a leading cause of irreversible blindness, characterized by progressive retinal ganglion cells (RGCs) loss. Increasing evidence links microglial activation and lipid metabolism dysregulation to neurodegeneration. However, the role of microglial lipid metabolic reprogramming in disease pathogenesis remains unclear. This study finds that microglia in an acute ocular hypertension (AOH) model exhibit abnormal lipid droplet accumulation, downregulation of low‐density lipoprotein receptor‐related protein 1 (LRP1), and a shift toward a pro‐inflammatory M1 phenotype. Importantly, serum samples from glaucoma patients reveal significantly reduced LRP1 levels compared to controls. To restore lipid homeostasis, this study develops alpinetin‐loaded PLGA nanoparticles (AlpNPs), which demonstrate efficient microglial uptake and sustained release. AlpNPs reduced intracellular lipid accumulation, promoted M2 polarization, and suppressed microglial proliferation and migration. Mechanistically, AlpNPs directly bind to LRP1 and enhance its interaction with PPARγ, thereby activating the downstream LXRα‐ABCA1 pathway, which is pivotal for cholesterol efflux and anti‐inflammatory responses. Knockdown of LRP1 abolished the protective effects of AlpNPs, confirming its essential role in mediating metabolic reprogramming. In vivo, intravitreal injection of AlpNPs significantly attenuates retinal inflammation and preserves RGCs in AOH. These findings identify microglial lipid metabolic dysfunction as a key driver in glaucoma and highlight LRP1‐targeted nanotherapy as a promising strategy for neuroprotection.