Mesenchymal Stem Cell-Derived Exosomes in Ophthalmology: A Comprehensive Review

“

TL;DR

This comprehensive review highlights that mesenchymal stem cell (MSC)-derived exosomes possess anti-inflammatory, anti-apoptotic, and neuroprotective properties similar to MSCs but with better safety and barrier penetration. Preclinical studies show efficacy in treating anterior segment diseases (corneal regeneration, dry eye, glaucoma) and posterior segment diseases (retinitis pigmentosa, diabetic retinopathy, age-related macular degeneration, uveitis). Clinical translation faces challenges including heterogeneity and lack of standardized protocols, but exosome-based therapies represent a promising alternative to conventional MSC transplantation.

Full summary

5,550 CHARS

**Background:** Mesenchymal stem cell (MSC) therapy has shown regenerative and immunomodulatory potential for ophthalmic diseases, but its clinical applicability is limited by suboptimal biocompatibility, penetration, and delivery to target ocular tissues, as well as risks such as allogeneic immunological rejection, unwanted differentiation, and vascular obstruction. MSC-derived exosomes, nano-sized extracellular vesicles (30–150 nm), have emerged as an alternative because they carry similar therapeutic cargo (proteins, miRNAs, lipids) and can penetrate biological barriers like the blood-retinal barrier, while avoiding many risks of cell-based therapy. This review summarizes studies from 2017–2022 on the characteristics, biological functions, and therapeutic potential of MSC-exosomes in anterior and posterior segment ocular diseases.

**Methods:** The authors conducted a narrative review of the literature, focusing on preclinical (in vitro and animal) studies and early-phase clinical trials. They examined exosome biogenesis, isolation (ultracentrifugation, ultrafiltration, microfluidic technologies), preservation (−80°C or cryopreservation), and routes of administration (intravitreal, subconjunctival, topical). Bioengineering strategies (transfection, electroporation, surface modification) to enhance drug delivery and targeting were also discussed.

**Key Results:** - **Corneal regeneration:** MSC-exosomes promoted corneal epithelial cell proliferation and migration in vitro, accelerated re-epithelialization in animal models, and reduced inflammation (downregulation of IL-1β, IL-8, TNF-α, NF-κB) and angiogenesis (downregulation of MMP-2, MMP-9, VEGF). miR-21 was identified as a key mediator via the PTEN/PI3K/Akt pathway. A thermosensitive hydrogel with miR-24-3p-rich exosomes improved corneal healing in an alkali burn rabbit model. - **Dry eye disease (DED):** In mouse models of graft-versus-host disease (GVHD)-associated DED, topical MSC-exosomes increased tear secretion, preserved goblet cells, reduced corneal defects, and shifted macrophages from M1 to M2 phenotype via miR-204. A phase 1/2 clinical trial (NCT04213248) in 14 patients (28 eyes) with refractory GVHD-DED showed significant reduction in corneal epithelial damage and symptom relief after 14 days of 10 µg/µL exosome eye drops four times daily, with no intraocular pressure changes or complications. - **Glaucoma:** Intravitreal MSC-exosomes increased retinal ganglion cell (RGC) survival in glaucomatous and optic nerve crush animal models, attributed to suppression of cis p-tau accumulation, miRNA modulation (miR-21, miR-146a, miR-17-92), and secretion of neurotrophic factors. In vitro, exosomes reduced oxidative stress in human trabecular meshwork cells (hTMCs) exposed to H₂O₂ (0.1 mM), decreasing iROS and proinflammatory cytokines (IL-1α, IL-1β, IL-6, IL-8) and upregulating MMP-2 and MMP-3. - **Retinitis pigmentosa (RP):** In MNU-induced photoreceptor injury mouse models, intravitreal MSC-exosomal miR-21 suppressed photoreceptor apoptosis for 1–2 months. In Rd10 mice, MSC-exosomes improved electroretinogram (ERG) and optokinetic tracking, increased outer nuclear layer thickness, and decreased TUNEL-positive nuclei and proinflammatory cytokines. miR-146a-Nr4a3 axis was implicated. - **Diabetic retinopathy (DR):** In streptozotocin-induced diabetic rabbits, MSC-exosomes via intraocular administration regenerated retina into well-defined layers. miR-222, miR-126, miR-486-3p, miR-17-3p, and miR-146a were identified as key mediators reducing inflammation, oxidative stress, and angiogenesis. For example, miR-126-overexpressing exosomes suppressed hyperglycemia-induced inflammation in human retinal endothelial cells and diabetic rats. - **Age-related macular degeneration (AMD):** In blue light-injured RPE cells and laser-induced CNV rat models, MSC-exosomes downregulated VEGF-A mRNA and protein, reduced damage, and improved histological structures. miR-27-3p was shown to suppress subretinal fibrosis via epithelial–mesenchymal transition inhibition. - **Uveitis:** In experimental autoimmune uveitis (EAU) models, intravenous or periocular MSC-exosomes reduced Th1 and Th17 cells, increased Tregs, and lowered clinical and pathological scores. IL-10-overexpressing exosomes enhanced these effects. Rapamycin-loaded exosomes improved drug delivery within 24 hours via subconjunctival injection. - **Idiopathic macular hole:** In a pilot study of 7 patients (51–71 years), 5 received MSC-exosomes after vitrectomy; 6 of 7 macular holes closed, and best-corrected visual acuity improved in 5 patients.

**Clinical Implications:** MSC-exosome therapies offer a safer, more versatile alternative to MSC transplantation, with potential for topical or less invasive administration due to their ability to penetrate ocular barriers. Early clinical data in GVHD-DED show safety and efficacy. However, challenges remain: heterogeneity in exosome products from different MSC sources (bone marrow, adipose, umbilical cord), lack of standardized isolation and quality control protocols, and need for large-scale production. Strategies to overcome these include using human pluripotent stem cell-derived MSCs, 3D culture systems, and preconditioning (hypoxia, cytokines). Donor selection based on genetic biomarkers (e.g., GSTT1 deletion), age, BMI, and cell-surface markers (STRO-1, nestin, CD146) may improve consistency. Further preclinical and clinical studies are needed to establish optimal dosing, routes, and long-term safety.