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Retinal Organoid–Based Evaluation of Icariin-Loaded Extracellular Vesicles for Hypoxia-Induced Retinal Injury via Mitochondrial Modulation

ABSTRACT: Background: Hypoxic injury is a critical pathological factor in various retinal degenerative diseases, leading to mitochondrial dysfunction and irreversible loss of retinal neurons. This study investigated the neuroprotective potential of Icariin-loaded extracellular vesicles (EV_ICA) using both R28 retinal progenitor cells and human embryonic stem cell (hESC)-derived retinal organoids. Methods: EV_ICA were isolated and characterized by morphology, EV marker expression, and zeta potential analysis. A CoCl₂-induced hypoxic injury model was established in R28 cells and hESC-derived retinal organoids to evaluate the therapeutic effects of EV_ICA. Gene and protein expression analyses, bulk RNA sequencing (RNA-seq), gene set enrichment analysis (GSEA), mitochondrial ROS measurements, and intracellular ATP assays were performed to assess neuroprotective efficacy and mitochondrial function. Results: EV_ICA exhibited typical spherical morphology, expressed standard EV markers, and showed a shift toward a less negative zeta potential compared to Naïve EV. In hypoxia-injured retinal models, EV_ICA significantly restored the expression of key retinal and neuroprotective markers, including Syntaxin12, NeuN, Vegf, Rbpms, Brn-3a, and Bdnf, while suppressing Hif-1α accumulation. Transcriptomic and GSEA analyses revealed that EV_ICA reactivated biological pathways associated with phototransduction, visual perception, and retinal development that were impaired under hypoxic conditions. Furthermore, EV_ICA improved mitochondrial homeostasis by up-regulating mitochondrial-related genes, reducing mitochondrial ROS accumulation, and recovering intracellular ATP production. Conclusion: These findings demonstrate that EV_ICA exerts neuroprotective effects by preserving mitochondrial quality control and restoring functional retinal gene programs under hypoxic stress. EV_ICA may therefore serve as a promising therapeutic candidate for hypoxia-related retinal degeneration and provide potential applications for cell-free regenerative medicine

ORGANISM(S): Homo sapiens

PROVIDER: GSE345168 | GEO | 2026/08/31

REPOSITORIES: GEO

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Project description:Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly, driven by retinal pigment epithelium (RPE) dysfunction, mitochondrial impairment, oxidative stress, chronic inflammation, and cellular senescence. Vutiglabridin, an orally available derivative of glabridin, has been reported to enhance mitochondrial function and mitigate metabolic stress, suggesting potential therapeutic utility in retinal aging. Here, we evaluated the efficacy and mechanism of Vutiglabridin in multiple models, including naturally aged mice representing age-associated retinal degeneration, sodium iodate (NaIO3)-induced geographic atrophy (GA), and laser-induced choroidal neovascularization (CNV). Retinal morphology and function were assessed by fundus photography, autofluorescence imaging, and electroretinography, while molecular, histological, and transcriptomic analyses were employed to investigate senescence, mitochondrial function, and inflammation. Pharmacokinetic profiling demonstrated prolonged ocular distribution of Vutiglabridin. In parallel, Paraoxonase 2 (PON2) knockdown mice were used to determine the mechanistic dependency. Vutiglabridin attenuated senescence and inflammatory markers, reduced mitochondrial ROS, and preserved retinal thickness in aged mice, while bulk RNA sequencing demonstrated partial reversal of aging-associated transcriptional signatures. In the NaIO3 model, Vutiglabridin restored mitochondrial membrane potential, enhanced mitophagy, and improved retinal function. In CNV models, it suppressed lesion growth and oxidative stress with efficacy comparable to aflibercept. Importantly, Vutiglabridin increased PON2 protein levels in vivo, and its protective effects were abolished in PON2-deficient mice, confirming a PON2-dependent mechanism. These findings establish Vutiglabridin as a promising oral therapeutic candidate for both dry and neovascular AMD, acting through PON2-mediated enhancement of mitochondrial resilience and suppression of oxidative, inflammatory, and senescent pathways.

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Retinal Organoid–Based Evaluation of Icariin-Loaded Extracellular Vesicles for Hypoxia-Induced Retinal Injury via Mitochondrial Modulation

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