Corneal nerves play a crucial role in maintaining ocular surface homeostasis by supporting the functional integrity of corneal epithelial, stromal, and endothelial cells; modulating tear secretion; and facilitating sensory responses essential for overall ocular health. With advancing age, these highly specialized peripheral sensory fibers undergo progressive attrition and morphologic distortion driven by the canonical hallmarks of aging including genomic instability, impaired proteostasis, mitochondrial dysfunction, and chronic low-grade inflammation. The resulting neuro-immune dysregulation reduces trophic support, delays wound healing, and predisposes older adults to dry-eye disease, neurotrophic keratopathy, and postsurgical hypoesthesia. Age-exacerbating cofactors including diabetes, dyslipidemia, neurodegenerative disorders, topical preservatives, chronic contact-lens wear, herpes zoster ophthalmicus, and ocular-surface hypoxia further accelerate sub-basal nerve rarefaction and functional decline. This review provides an overview of age-related physiological alterations in ocular surface nerves, with a particular emphasis on corneal innervation. It also discusses risk factors that speed up these changes. Given the inherently limited regenerative capacity of corneal nerves and their inability to fully restore to baseline conditions following injury or degeneration, it is critical to identify and develop effective strategies aimed at mitigating or delaying physiological nerve degeneration and promoting nerve regeneration. This review also brings up emerging therapeutic strategies, including regenerative medicine, neuroprotective agents, and lifestyle interventions aimed at mitigating age-related corneal nerve degeneration.

Corneal regeneration has gained growing interest in recent years, largely due to the limitations of conventional treatments and the persistent shortage of donor tissue. Among the emerging strategies, extracellular vehicles (EVs), especially those derived from mesenchymal stromal cells (MSCs), have shown great promise as a cell-free therapeutic approach. These nanoscale vesicles contribute to corneal healing by modulating inflammation, supporting epithelial and stromal regeneration, and promoting nerve repair. Their therapeutic potential is largely attributed to the diverse and bioactive proteomic cargo they carry, including growth factors, cytokines, and proteins involved in extracellular matrix remodeling. This review presents a comprehensive examination of the proteomic landscape of EVs in the context of corneal regenerative medicine. We explore the biological functions of EVs in corneal epithelial repair, stromal remodeling, and neurodegeneration. In addition, we discuss advanced proteomic profiling techniques such as mass spectrometry (MS) and liquid chromatography–mass spectrometry (LC-MS/MS), which have been used to identify and characterize the protein contents of EVs. This review also compares the proteomic profiles of EVs derived from various MSC sources, including adipose tissue, bone marrow, and umbilical cord, and considers how environmental cues, such as hypoxia and inflammation, influence their protein composition. By consolidating current findings, this article aims to provide valuable insights for advancing the next generation of cell-free therapies for corneal repair and regeneration.