Single‐Cell Transcriptome Analysis Reveals That Hmga2 Regulates Neuroinflammation and Retinal Function by Modulating Müller Cell Autophagy Through PI3K/AKT Signaling Following MCAO‐Induced Retinal Ischemia

Central retinal artery occlusion (CRAO) can lead to retinal ischemia (RI), resulting in painless vision impairment. Müller cells, the principal supporting glial cells of the retina, are distributed throughout its layers and play pivotal roles in maintaining retinal homeostasis by regulating inflammation, oxidative stress, and angiogenesis following RI. However, the specific role of Müller cells in RI induced by middle cerebral artery occlusion (MCAO) remains unclear. In this study, single-nucleus RNA sequencing is employed to investigate transcriptional changes in various retinal cell types following MCAO-induced RI. A novel Müller cell subpopulation, characterized by the highest expression of the high-mobility group A2 gene (Hmga2), emerged after RI. Knockout of Hmga2 alleviated neuroinflammation and RI-related symptoms, potentially through binding to phosphoinositide 3-kinase and regulating Müller cell autophagy. Based on these findings, a targeted strategy using hybrid nanoparticles composed of Müller cell membranes and liposomes-termed siRNA-Hmga2@LMM-is developed to deliver siRNA against Hmga2. In vivo experiments revealed that intravitreal injection of siRNA-Hmga2@LMM improved retinal function following RI. These findings provide new mechanistic insights and identify potential targets for the treatment of RI.