Quercetin-Loaded Exosomes Halt Myopia Progression by Blocking Ferroptosis and ER Stress
A novel exosome drug delivery system loaded with quercetin matches atropine's efficacy in slowing myopia, targeting scleral fibroblast cell death pathways.
Summary
Researchers engineered quercetin-loaded exosomes (Exo-Que) to overcome quercetin's poor water solubility and low ocular bioavailability. Tested in a guinea pig form-deprivation myopia model, Exo-Que eye drops reduced refractive error progression by ~59% and axial length growth by ~36–38% over two to four weeks—comparable to 0.1% atropine. Mechanistically, Exo-Que suppressed endoplasmic reticulum stress via the IRE1-XBP1, PERK-eIF2, and ATF6 pathways, and inhibited ferroptosis by modulating GRP78 interactions with ACSL4 and GPX4. These combined actions reduced scleral extracellular matrix remodeling. The system showed excellent biosafety in both cell and animal studies, suggesting a promising, natural-product-based topical therapy for myopia control.
Detailed Summary
Myopia is a rapidly escalating global health burden driven in large part by scleral extracellular matrix (ECM) remodeling—a process that weakens the eye's structural support and allows axial elongation. Scleral fibroblasts are the primary cells responsible for this remodeling, yet effective pharmacological strategies targeting them remain limited. Two emerging mechanisms—endoplasmic reticulum (ER) stress and ferroptosis—have separately been implicated in fibrotic ECM changes, but their combined roles in myopia had not been therapeutically exploited.
The researchers developed Exo-Que by loading quercetin, a natural flavonoid with well-documented anti-fibrotic and antioxidant properties, into exosomes derived from human umbilical cord mesenchymal stem cells (HUCMSCs). Quercetin's hydrophobicity has historically limited its clinical use; encapsulation in exosomes dramatically improved aqueous solubility, corneal permeability, and precorneal retention time. Characterization confirmed typical exosome morphology (~100 nm), positive exosomal markers (CD9, CD81, TSG101, Alix), high entrapment efficiency, and sustained quercetin release over 48 hours. Storage stability at −80°C was maintained for at least 30 days.
In a guinea pig form-deprivation myopia (FDM) model, topical Exo-Que eye drops (six times daily, 10 µL/dose) achieved reductions of 58–60% in refractive error progression and 36–38% in axial length growth at both two- and four-week timepoints. Critically, this efficacy was statistically comparable to the gold-standard clinical agent 0.1% atropine, while blank exosomes alone produced no significant effect. In vitro, quercetin and Exo-Que suppressed tunicamycin-induced ER stress by downregulating IRE1-XBP1 and PERK-eIF2α signaling branches, and reduced ATF6 activation. On the ferroptosis axis, Exo-Que modulated protein–protein interactions between the ER chaperone GRP78 and both ACSL4 (a pro-ferroptotic lipid metabolism enzyme) and GPX4 (the master antioxidant guardian), thereby reducing lipid peroxidation, iron accumulation, and MDA levels while preserving glutathione. Together, these actions curtailed collagen degradation and MMP activity, preserving scleral ECM integrity.
Biosafety evaluations were thorough: CCK-8 assays and scratch-wound healing studies in human corneal epithelial cells showed no cytotoxicity or impaired proliferation at therapeutic concentrations. In vivo, slit-lamp examination, corneal fluorescein staining, H&E histology, and major organ pathology in treated guinea pigs revealed no adverse effects after four weeks of use.
This work represents the first report of an exosome-based drug delivery system applied to myopia prevention, and provides mechanistic evidence linking ER stress-driven ferroptosis to scleral ECM remodeling. The dual-pathway inhibition strategy—using a single food-derived molecule delivered in a biocompatible nanocarrier—offers an appealing alternative or complement to atropine, particularly for populations seeking non-pharmacological or lower-side-effect options. Translation to humans will require further pharmacokinetic studies and clinical trials.
Key Findings
- Exo-Que eye drops reduced myopia progression by ~59% in refractive error and ~36–38% in axial length growth, matching 0.1% atropine efficacy.
- Quercetin encapsulation in HUCMSCs-derived exosomes overcame its hydrophobicity, enhancing corneal permeability and precorneal retention.
- Exo-Que suppressed ER stress through IRE1-XBP1, PERK-eIF2α, and ATF6 pathway inhibition in scleral fibroblasts.
- Ferroptosis in scleral fibroblasts was blocked via modulation of GRP78-ACSL4 and GRP78-GPX4 protein interactions, reducing lipid peroxidation.
- No cytotoxicity, corneal damage, or organ pathology was observed in either in vitro or 4-week in vivo safety evaluations.
Methodology
Guinea pig form-deprivation myopia model (n=55 per key group) received topical Exo-Que, blank exosomes, or 0.1% atropine six times daily for 2 or 4 weeks; refraction and axial length were measured by infrared photorefractor and A-scan ultrasonography. In vitro mechanistic studies used human scleral fibroblasts treated with tunicamycin to induce ER stress, with pathway analysis via western blot, co-immunoprecipitation, and ferroptosis biomarker assays (GSH, MDA, iron).
Study Limitations
All efficacy data derive from a guinea pig FDM model, which may not fully replicate human myopia mechanisms or pharmacokinetics. The study did not include dose-ranging comparisons beyond a single Exo-Que concentration or evaluate long-term ocular toxicity beyond four weeks. Human clinical translation requires pharmacokinetic profiling, scaled exosome manufacturing validation, and randomized controlled trials.
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