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Engineered mesenchymal stem cell-derived extracellular vesicles attenuate acute glaucoma-induced neuroinflammation by
Aixiang Luo1, Haiyang Yu2, Tianqi Duan3
1Department of Anatomy and Neurobiology, Xiangya School of Basic Medical Sciences, Central South University, 410013 Changsha, PR China.
Abstract:
Retinal microglia-mediated neuroinflammation is a critical driver of pathological damage in glaucoma, leading to irreversible loss of retinal ganglion cells (RGCs). Current treatments remain limited in effectively targeting and modulating this neuroinflammatory component within the retinal microenvironment. To address this, we engineered cRGD peptide-functionalized mesenchymal stem cell (MSC)-derived extracellular vesicles (cRGD-EVs) capable of actively targeting activated microglia for the localized delivery of anti-inflammatory miRNAs. After intravitreal administration, cRGD-EVs demonstrated enhanced accumulation in the retina and specific uptake by activated microglia in a rat model of retinal ischemia/reperfusion (RIR) injury. Both in vitro co-culture models and in vivo analyses confirmed the targeting efficacy and phenotypic reprogramming of microglia from a pro-inflammatory (M1) to an anti-inflammatory (M2) state. Intravitreal injection of cRGD-EVs loaded with key miRNAs (let-7c-5p, miR-21a-5p, and miR-146a-5p) significantly suppressed NF-κB pathway activation and reduced the expression of downstream pro-inflammatory cytokines. Treated animals exhibited notable preservation of retinal structure, increased RGC survival, and significant recovery of visual function, as measured by electroretinography. Furthermore, in acute ocular hypertension model, cRGD-EV treatment attenuated glaucomatous neurodegeneration and improved overall retinal homeostasis. These findings highlight cRGD-EVs as a promising targeted biologic delivery system for treating neuroinflammatory components of glaucoma and potentially other retinal diseases characterized by microglial activation.
Insights
Targeted extracellular vesicles deliver anti-inflammatory microRNAs to retinal microglia, reducing neuroinflammation and preserving vision in glaucoma models. This approach offers a promising new therapy for retinal diseases.
Area of Science:
- Ophthalmology
- Neuroscience
- Biotechnology
Background:
- Neuroinflammation driven by retinal microglia is a key factor in glaucoma's progressive damage to retinal ganglion cells (RGCs).
- Existing glaucoma treatments struggle to effectively target and control retinal neuroinflammation.
- Mesenchymal stem cell-derived extracellular vesicles (EVs) offer potential for targeted drug delivery within the eye.
Purpose of the Study:
- To develop and evaluate cRGD peptide-functionalized EVs (cRGD-EVs) for targeted delivery of anti-inflammatory microRNAs (miRNAs) to activated microglia in glaucoma.
- To assess the efficacy of cRGD-EVs in modulating microglial phenotype and reducing neuroinflammation in preclinical models of glaucoma and retinal injury.
Main Methods:
- Engineered cRGD-EVs loaded with specific anti-inflammatory miRNAs (let-7c-5p, miR-21a-5p, miR-146a-5p).
- Intravitreal administration of cRGD-EVs in rat models of retinal ischemia/reperfusion (RIR) injury and acute ocular hypertension.
- In vitro co-culture and in vivo studies to confirm targeting, microglial reprogramming (M1 to M2), and assessment of neuroinflammation markers (NF-κB pathway, cytokines).
- Evaluation of RGC survival, retinal structure, and visual function (via electroretinography).
Main Results:
- cRGD-EVs showed enhanced retinal accumulation and specific uptake by activated microglia post-intravitreal injection.
- Confirmed targeting efficacy and successful reprogramming of microglia from a pro-inflammatory (M1) to an anti-inflammatory (M2) phenotype.
- cRGD-EV treatment significantly suppressed NF-κB activation, reduced pro-inflammatory cytokines, preserved retinal structure, increased RGC survival, and improved visual function.
- Attenuated glaucomatous neurodegeneration and improved retinal homeostasis in ocular hypertension models.
Conclusions:
- cRGD-EVs represent a novel, targeted biologic delivery system for treating microglial-mediated neuroinflammation in glaucoma.
- This strategy holds promise for managing glaucoma and other retinal diseases characterized by microglial activation.
- Targeted delivery of anti-inflammatory miRNAs via engineered EVs offers a potential therapeutic avenue for vision preservation.
