Retinal Pigment Epithelium Extracellular Vesicles Induce Microglia Polarization in MERTK-Associated Retinal Degeneration.

PURPOSE: Retinitis pigmentosa (RP) is a hereditary retinal disease. MERTK-associated RP is characterized by earlier onset and rapid progression, featuring retinal pigment epithelium (RPE) inflammation and microglial activation, yet the underlying mechanisms remain incompletely understood. The study aimed to elucidate the intrinsic interactions between RPE inflammation and microglial activation mediated by RPE-derived extracellular vesicles (EVs). METHODS: Induced pluripotent stem cell (iPSC)-derived RPE models from MERTK mutant patients and healthy controls were established and characterized by transcriptomic analysis. RPE-derived EVs were isolated, and their RNA and protein cargo were systematically profiled using transcriptomic and proteomic data, revealing a potential role in retinal inflammation regulation. The effects of RPE-EVs on microglial activation were confirmed through in vitro co-culture and in vivo animal experiments. RESULTS: Transcriptomic analysis revealed that differentially expressed genes between MERTK mut-RPE (M-RPE) and control RPE (C-RPE) were enriched in inflammatory signaling pathways and EV-related terms. Multi-omics data further indicated that the altered RNA and protein cargo of M-RPE-derived EVs were closely associated with inflammation and immune regulation. In vitro co-culture confirmed that M-EVs could rapidly activate microglia and upregulate pro-inflammatory factors. In vivo experiments indicated that microglia phagocytosed M-EVs exhibited more pronounced M1 polarization and migratory changes. CONCLUSIONS: RPE-derived EVs act as critical drivers of microglial M1 polarization in MERTK-associated RP. Our study revealed their pivotal role in the progression of early-onset severe RP, providing theoretical support for the potential of targeting EVs to modulate the retinal immune microenvironment and intervene in the progression of retinal degeneration.