Stem cell secretome- and extracellular vesicle-based therapies for retinal pathologies

Table 6 Disease-by-product-class evidence map for retinal secretome- and extracellular vesicle-based applications

Disease/application	Direct acellular evidence	Supportive/indirect evidence	Highest maturity	Interpretation
Diabetic retinopathy	Native MSC-derived sEVs[14,35,36]; engineered MSC-derived EVs[37]	Viable-MSC evidence[30]	Level 2	Among the broadest preclinical application areas; no controlled human retinal evidence
Inherited retinal degeneration/retinitis pigmentosa	MSC-derived EVs[15]; neural progenitor cell-derived EV preparations[24]	Paracrine/miRNA evidence[16]; non-stem-cell photoreceptor EV engineering[38]	Level 2	Multiple animal studies, with substantial product-, model-, and dose-level heterogeneity
Optic-nerve injury	MSC-derived EV/exosome preparation[25]	Viable-cell neuroprotective evidence[32]	Level 2	Preclinical evidence only
Dry AMD/oxidative RPE injury	MSC-derived exosome preparation[39]	iPSC-RPE complement evidence[40] provides disease context rather than EV therapeutic evidence	Level 1-2	Preclinical evidence primarily from experimental oxidative/toxic injury models
Neovascular retinal disease	Engineered MSC-derived exosome/EV approaches[26,33]		Level 2	Preclinical anti-angiogenic proof-of-concept, particularly for engineered products
Large/refractory macular hole	MSC-derived exosome subgroup in an uncontrolled surgical case series[41]	Concomitant PPV, ILM peeling, tamponade, and viable-MSC cases	Level 3	Only direct human retinal signal in the reviewed corpus; independent EV efficacy cannot be established
Other retinal/optic-nerve applications	Sparse or heterogeneous direct evidence	Viable-cell, non-stem-cell EV, or disease-context studies	Level 1-2 or insufficient	Least mature areas; disease-specific validation remains necessary

MSC: Mesenchymal stem cell; sEVs: Small extracellular vesicles; EV: Extracellular vesicle; miRNA: MicroRNA; AMD: Age-related macular degeneration; iPSC: Induced pluripotent stem cell; RPE: Retinal pigment epithelium; PPV: Pars plana vitrectomy; ILM: Internal limiting membrane.