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

Table 1 Bioactive factors of the stem cell secretome and relevance to retinal homeostasis and disease modulation

Secretome component	Representative cargo or mediators	Main retinal targets	Potential biological role in retinal disease	Translational relevance	Ref.
Soluble growth and trophic factors	VEGF, HGF, IGF-1, FGF-2, BDNF, NGF, TGF-β, and related neurotrophic mediators	Photoreceptors, retinal ganglion cells, RPE, Müller cells, and vascular cells	Support neuronal survival, tissue repair, stress resistance, and retinal microenvironmental homeostasis	May contribute to neuroprotective and disease-modifying effects without direct cell replacement	[19,20]
Cytokines and chemokines	Anti-inflammatory and immunomodulatory cytokines; regulators of TNF-α, IL-1β, NF-κB, and related pathways	Microglia, Müller cells, astrocytes, and infiltrating immune cells	Modulate neuroinflammation, reduce glial activation, and limit secondary inflammatory injury	Relevant to retinal degeneration, diabetic retinopathy, uveitis-related inflammation, and ischemic retinal injury	[12,21]
EVs and exosome-enriched fractions	EVs carrying proteins, lipids, metabolites, messenger RNA, microRNAs, long non-coding RNAs, and other regulatory molecules	RPE, photoreceptors, retinal ganglion cells, microglia, and endothelial cells	Transfer complex molecular cargo and regulate multiple pathways simultaneously	Represent a central platform for acellular regenerative therapy and engineered retinal delivery	[9-11]
Regulatory RNAs	MicroRNAs, long non-coding RNAs, and other regulatory non-coding RNAs	Microglia, photoreceptors, RPE, and endothelial cells	Regulate inflammation, apoptosis, oxidative stress, angiogenesis, and cell-survival pathways	Candidate therapeutic cargoes for disease-specific or engineered EV products	[15-17]
Proteins and enzymes	Antioxidant, anti-apoptotic, extracellular matrix-related, and signaling proteins; pathway regulators such as NEDD4	RPE, retinal neurons, glial cells, and vascular cells	Influence oxidative stress, apoptosis, autophagy, necroptosis, extracellular matrix remodeling, and cellular signaling	May serve as potency markers or mechanistic mediators of therapeutic activity	[14,28]
Lipids and metabolites	Bioactive lipids, metabolic intermediates, and membrane-associated molecules	Retinal neurons, RPE, vascular cells, and immune cells	Support membrane signaling, metabolic regulation, intercellular communication, and adaptation to cellular stress	May influence EV biodistribution, cellular uptake, and biological activity	[9,10]
Engineered or preconditioned secretome products	Hypoxia-primed EVs, cargo-loaded EVs, surface-modified vesicles, and peptide-targeted EVs	Disease-specific retinal cell populations	Enhance cellular targeting, modify cargo composition, and increase therapeutic potency	Promising, but requiring standardization, biodistribution studies, potency testing, and long-term safety validation	[22,23,27]

VEGF: Vascular endothelial growth factor; HGF: Hepatocyte growth factor; IGF-1: Insulin-like growth factor-1; FGF-2: Fibroblast growth factor 2; BDNF: Brain-derived neurotrophic factor; NGF: Nerve growth factor; TGF-β: Transforming growth factor β; RPE: Retinal pigment epithelium; TNF-α: Tumor necrosis factor α; IL-1β: Interleukin-1β; NF-κB: Nuclear factor kappa B; EV: Extracellular vesicle; NEDD4: Neuron-expressed developmental downregulation 4.