Macrophage Extracellular Vesicles: Therapeutic Strategies for Corneal Fibrosis in Rare Diseases

Corneal scarring (fibrosis) is a blinding condition affecting millions of sufferers worldwide. It is not only in common ocular injuries but also in genetically inherited rare diseases such as epidermolysis bullosa (EB), keratitis-ichthyosis-deafness (KID) syndrome and aniridia. In rare diseases like EB or KID syndrome, corneal fibrosis arises from chronic inflammation, structural instability and neuro-immune dysfunction driven by genetic mutations. Current therapies are not effective in addressing the needs of affected individuals due to limited efficacy nor the considerable side effects of treatment. Extracellular vesicles (EVs) from various cell types such as mesenchymal stem cells not only possess high biocompatibility but have shown promising results in limiting corneal fibrosis. Rather than targeting a single molecular signaling pathway, EVs which contain regulatory RNAs and proteins are hypothesized to target multiple pathways synergistically. Macrophage-derived EVs (Mac-EVs) with an immunomodulatory nature may offer a promising therapeutic effect for rare diseases. Various EV delivery platforms have been proposed in preclinical studies. However, not all of these delivery techniques are appropriate for the cornea in rare diseases. In this review, we delineate recent advances in understanding corneal fibrosis from a rare disease point of view, including the impact on corneal immune cells and nerves. We then provide critical considerations of therapeutic development for corneal fibrosis in rare diseases. Furthermore, we used this knowledge to comprehensively consider the various EVs, especially Mac-EVs, synthesis methods and delivery techniques. Ultimately, this review aims to enable biomolecule researchers to develop EV-based therapies that not only exert anti-fibrotic effects but also address clinical compatibility for corneal fibrosis in rare diseases.