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

Table 3 Conceptual advantages and current limitations of secretome- and extracellular vesicle-based therapies compared with conventional cell-based approaches

Domain	Potential benefits of secretome- and EV-based therapy	Current limitations	Practical implication	Ref.
Therapeutic concept	Acellular approach based on paracrine signaling rather than direct cell replacement	Does not replace lost photoreceptors, RPE, or retinal architecture	More realistic as a disease-modifying or adjunctive strategy than as a complete regenerative cure	[3,7,12]
Safety profile	Avoids administration of viable proliferative cells	Long-term ocular safety, immunogenicity, toxicity, and off-target effects remain insufficiently defined	May reduce some risks associated with cell transplantation, but still requires rigorous preclinical and clinical safety testing	[3,41]
Immunological risk	Potentially lower risk of immune rejection compared with living donor cells	EV cargo may still trigger inflammatory or immune responses depending on its source and biological context	Source, purity, and inflammatory profile must be carefully characterized	[8,41]
Tumorigenic and differentiation risk	Avoids uncontrolled proliferation, ectopic differentiation, and tumor formation associated with viable cell grafts	Bioactive cargo may still have unintended effects on proliferation, angiogenesis, or fibrosis	Functional potency assays are required in addition to particle counting and marker analysis	[3,4,11]
Biological activity	Can deliver proteins, lipids, metabolites, mRNA, microRNAs, and other regulatory molecules	Cargo composition is heterogeneous and highly dependent on donor-cell source, culture conditions, and isolation methods	Batch-to-batch reproducibility is a central translational requirement	[9,10,12]
Mechanistic breadth	May simultaneously modulate inflammation, oxidative stress, apoptosis, angiogenesis, glial activation, and neuronal survival	Multifactorial effects make it difficult to identify the active components and dominant mechanisms	Mechanism-specific validation is required for each disease model	[7,12,17]
Manufacturing and storage	Potentially easier to isolate, store, standardize, and administer than living-cell products	Scalable production, purification, storage stability, and quality control have not yet been standardized	GMP-compatible workflows and validated release criteria are required	[11,49,51]
Engineering potential	EVs can be loaded or modified with selected RNAs, proteins, peptides, or surface ligands	Engineering may alter biodistribution, potency, safety, and regulatory classification	Engineered products require separate validation from native secretome or EV preparations	[23,27,48]
Retinal delivery	Small vesicular carriers may protect their cargo and facilitate intraocular delivery	Retinal penetration, cell-specific uptake, optimal route, dose, and clearance remain unresolved	Intravitreal, subretinal, suprachoroidal, and biomaterial-assisted delivery approaches should be compared systematically	[42,43,45]
Clinical evidence	Strong mechanistic rationale and encouraging preclinical findings across several retinal disease models	Human evidence remains limited and heterogeneous and does not demonstrate durable visual restoration	Clinical translation should proceed cautiously using disease-specific structural and functional endpoints	[13,41]
Disease-stage suitability	May be useful when viable retinal cells remain responsive to trophic, anti-inflammatory, or vascular-stabilizing signals	Benefits are likely to be limited in advanced disease with extensive photoreceptor or RPE loss	These therapies may be better positioned for early or intermediate disease or for combination treatment	[1,3,4]
Combination potential	May complement gene therapy, anti-VEGF therapy, neuroprotective drugs, biomaterials, or cell-replacement strategies	Optimal combinations, timing, sequencing, and patient selection remain unknown	Future studies should define whether each product is primarily neuroprotective, immunomodulatory, vascular-stabilizing, or delivery-enhancing	[3,23,46]

EV: Extracellular vesicle; RPE: Retinal pigment epithelium; VEGF: Vascular endothelial growth factor; GMP: Good manufacturing practice.