Published online Oct 26, 2026. doi: 10.4252/wjsc.125852
Revised: August 24, 2026
Accepted: October 20, 2026
Published online: October 26, 2026
Processing time: 100 Days and 19.1 Hours
Retinal vascular disorders and degenerative disorders are causes of irreversible vision loss. Many of the treatments available for them can slow the disease but cannot fix the retinal damage that has already taken place. Viable stem cell trans
Core Tip: Stem cell secretome and extracellular vesicles are under exploration as acellular therapeutic approaches for retinal disease. Their biological activity appears to depend largely on the transfer of trophic factors, proteins, lipids, and regulatory RNAs that can influence inflammation, oxidative stress, apoptosis, vascular homeostasis, and neuronal survival. Although the findings reported to date are encouraging, most of the available evidence remains preclinical. Before these products can enter routine retinal care, substantial work is still needed to standardize their production and characterization, define appropriate dosing, establish reliable potency assays, and assess long-term safety.
- Citation: Capobianco M, Cappellani F, Enaholo ES, Zeppieri M. Stem cell secretome- and extracellular vesicle-based therapies for retinal pathologies. World J Stem Cells 2026; 18(10): 125852
- URL: https://www.wjgnet.com/1948-0210/full/v18/i10/125852.htm
- DOI: https://dx.doi.org/10.4252/wjsc.125852
Retinal degenerative diseases consist of a heterogeneous group of inherited and acquired disorders, including retinitis pigmentosa (RP), Stargardt disease, age-related macular degeneration (AMD), and diabetic retinopathy (DR), that can cause irreversible vision loss. Although they have different causes, the outcomes of these diseases are often similar due to the loss of photoreceptors and retinal pigment epithelium (RPE), as well as dysfunction of retinal neurovascular and glial cells, oxidative stress, and inflammation. Vascular dysregulation and disruption of retinal homeostasis also occur[1,2]. Because existing therapies usually slow disease progression instead of regenerating damaged retinal tissue, increasing interest is being shown in regenerative strategies aimed at preserving viable cells and modulating the retinal microenvironment.
Due to their regenerative potential and ability to develop into various cell types, stem cells are highly attractive in the field of regenerative medicine. Some therapeutic effects may arise from short-term paracrine signaling instead of long-term engraftment or cell replacement[2-4]. According to systematic reviews and meta-analyses, stem cell therapy may provide visual benefits in some eye diseases, such as AMD, Stargardt disease, and RP, but these reports are based on limited evidence. This is because the available studies generally had small samples and differed in their cell sources, routes of delivery, and follow-up[5,6]. Due to these limitations, interest in acellular approaches based on the stem cell secretome and extracellular vesicles (EVs) has increased[7,8]. For clarity, throughout this review, “stem cell therapy” refers to strategies involving the administration or transplantation of viable stem or progenitor cells, whereas “secretome- or EV-based therapy” refers to acellular products derived from stem-cell paracrine activity; these approaches are therefore discussed separately and should not be considered interchangeable[3,7,8].
The secretory products of stem cells contain compounds that can influence cell survival and immunity, together with EVs that can transfer RNA and other important biomolecules to recipient cells[7-10]. According to recent consensus guidelines, it is recommended that EV remains the broader term unless endosomal origin is demonstrated; in that case, the term exosome may be appropriate[10,11]. Stem cell-derived EVs have shown anti-inflammatory, anti-apoptotic, neuroprotective, and vascular effects in retinal models across different diseases[7,12]. They may mitigate certain risks associated with immune rejection, ectopic proliferation, and tumorigenicity when compared with viable-cell approaches. However, this still requires rigorous standards for source material, production, isolation, characterization, dosing, and functional assays[8,10-13].
The main rationale for retinal application comes from preclinical evidence. Mesenchymal stem cell (MSC)-derived EVs have decreased oxidative stress and apoptosis in models of DR via neuron-expressed developmental downregulation 4 (NEDD4)/PTEN/protein kinase B (AKT)/nuclear factor erythroid 2-related factor 2 (NRF2) signaling[14], preserved photoreceptors in rd10 mice via miR-146a/Nr4a3-mediated anti-inflammatory effects[15], and decreased photoreceptor apoptosis via exosomal miR-21[16]. EV-associated noncoding RNAs are also being investigated for their role in regulating angiogenesis and inflammation[17]. Nonetheless, there is considerable heterogeneity in the evidence involving disease models, cell sources, EV preparations, delivery routes, and outcome measures.
Related literature has also addressed retinal organoid platforms[18], secretome-based regenerative approaches[19,20], retinal EV biology[21], MSC-derived EV preconditioning and engineering[22,23], and representative preclinical retinal applications[24-26]. Consequently, this narrative review offers a critical appraisal of the biological rationale, preclinical and early translational evidence, delivery strategies, and bioengineering of stem cell secretome- and EV-based therapies for retinal disease. Particular attention is given to standardization, reproducibility, biodistribution, safety, and the distinction between plausible disease-modifying effects and established clinical utility. Rather than considering secretome-derived products as a single therapeutic category, this review distinguishes non-vesicular soluble secretome components, EV preparations, exosome-enriched fractions, and engineered EV platforms. This framework allows their biological composition, mechanisms, translational requirements, and therapeutic positioning to be evaluated separately, while distinguishing disease-modifying effects from claims of structural retinal regeneration or established clinical utility[9-11,19].
Recent reviews have addressed EV biology in degenerative retinal disease[2], retinal EV therapeutics more broadly[7,12], MSC-derived EV/exosome applications across ophthalmology[8,13], and engineered exosome approaches in ocular vascular disease[27]. The present review complements these publications by organizing the evidence according to product class, explicitly separating direct acellular evidence from indirect viable-cell evidence, and linking study-level product and model heterogeneity to translational readiness. The main intercellular signaling mechanisms and retinal pathways discussed in the review are outlined in Figure 1.
A focused narrative literature search was performed using PubMed/MEDLINE and last updated on August 26, 2026, the evidence cut-off for this review. The main search on PubMed made use of the following Boolean combination: (“stem cell secretome” OR “conditioned medium” OR “extracellular vesicles” OR exosomes OR “small extracellular vesicles”) AND (retina OR “retinal degeneration” OR “retinitis pigmentosa” OR “age-related macular degeneration” OR “diabetic retinopathy” OR “retinal ischemia” OR “optic nerve injury”). No limit was set on the number of citations or the type of publication. For the contemporary synthesis, a preference was given to English-language papers published from 2020 until the evidence cut-off, but earlier seminal studies were retained when required for essential biological, methodological, or clinical context. Backward citation chaining from systematic reviews, meta-analyses, and key original experimental or translational papers was used to identify additional publications.
Any scientific publication that reported on the stem-cell secretome, conditioned medium, EVs, or source-study-defined exosome preparations in retinal or optic-nerve disease was eligible for the overall narrative corpus. Also eligible were papers on biological mechanisms relevant to retinal neuroprotection, inflammation, oxidative stress, apoptosis, angiogenesis, RPE dysfunction, photoreceptor or retinal ganglion cell (RGC) injury. Lastly, publications on delivery, bioengineering, characterization, manufacturing, or regulatory matters relevant to translational development were also considered. The narrative synthesis was open to reviews, systematic reviews, meta-analyses, consensus or methodological papers, original preclinical studies, translational investigations, and early human reports. Papers were excluded if they were not related to retinal or optic-nerve disease or did not have direct biological, therapeutic, methodological, or translational relevance. Viable-cell studies were retained only when relevant to paracrine mechanisms. They were classified as indirect support rather than direct evidence of acellular therapeutic efficacy.
Studies involving non-stem-cell-derived EVs were kept only where they provided clearly labeled supportive proof-of-concept information relevant to EV engineering, retinal delivery, or disease biology. The final narrative corpus consisted of 52 publications. The original experimental and clinical studies, reviews, methodological papers, and translational literature did not represent 52 homogeneous therapeutic studies selected through a systematic-review process and should not be so interpreted. Since this was an iterative narrative review rather than a prospectively registered systematic review, a prospective PRISMA-style screening and exclusion log was not generated, and no formal quantitative risk-of-bias assessment or meta-analysis was conducted. In the interest of improving reproducibility without imposing a systematic-review design retrospectively, we now state explicitly our eligibility rules, evidence categories, and study-level extraction procedures.
For the study-level evidence synthesis, original reports used for direct comparison were evaluated by means of a predefined extraction grid that included disease/model, evidence level, product identity and cellular source, preparation and characterization, route of administration, source-reported dose metric, comparator, sample size, follow-up, principal endpoints, main findings, and main methodological limitations. During revision, each extracted study entry was cross-checked with the respective primary report. Numerical values were transcribed only when explicitly reported in the primary source; otherwise, they were noted as NR (not reported). Dose units were maintained verbatim as reported and were categorized as either particle number, protein mass or concentration, conditioned-medium volume, or other source-defined metrics. Conversion between non-equivalent dose metrics was not performed. According to MISEV2023, EV is the generic term to use when the biogenesis of vesicles is not established. The source-study use of the term “exosome” is retained when reproducing the terminology of the original report; hence, it does not represent independent confirmation of endosomal origin[11].
The stem cell secretome is comprised of bioactive components released into the extracellular space; it contributes to the therapeutic properties of stem cells. Components of the secretome include trophic factors, chemokines, cytokines, enzymes, extracellular matrix (ECM) proteins, lipid mediators, metabolites, nucleic acids, and EVs. These mediators may regulate tissue homeostasis, angiogenesis, apoptosis, ECM remodeling, inflammation, and immune responses[19]. Secretome composition varies according to the cellular source, differentiation state, culture conditions, isolation methods, and microenvironmental stimuli[19]. Among its vesicular components, EV preparations, including exosome-enriched fractions, have drawn interest for their capacity to transfer complex molecular cargo to recipient cells[9-11]. For this review, conditioned medium refers to the culture supernatant remaining after cellular debris have been removed. It may include soluble and vesicular components unless fractionated subsequently. A soluble secretome fraction refers to the non-vesicular portion that has been separated from EVs, while an EV-enriched fraction indicates a preparation that is enriched in vesicles but not necessarily highly purified. Purified EV preparations are those which are made by appropriate vesicle isolation/purification and characterization procedures. The term small EVs (sEVs) applies to operationally size-defined sEV preparations according to MISEV terminology, while engineered EV products include vesicles modified through parental-cell engineering, exogenous cargo loading or surface functionalization. These product categories are therefore not regarded as substitutable[11,19,23].
Exosomes are a subtype of endosomal sEVs. Their size mostly ranges from 40 nm to 160 nm; and they develop through endosomal maturation, intraluminal vesicle formation within multivesicular compartments, and eventual release after integrating with the plasma membrane[9]. EV preparations are heterogeneous and most isolation methods have no proven biogenesis; nonetheless, current consensus recommends the designation “EV” or “small EVs” as broader terms unless endosomal origin is precisely demonstrated[11]. EV cargo may include proteins, lipids, metabolites, DNA, messenger RNA, microRNAs, long non-coding RNAs, and other RNA subtypes expressing characteristics of the source cell and its physiological state. EVs are thus, now considered much more than cellular waste by-products; they are regarded as active mediators of intercellular communication with potential biologic, and therapeutic significance[9,10].
EVs are particularly pertinent to retinal disorders due to their capacity for transferring diverse molecular components[7,12]. Retinal diseases are multifactorial, often leading to up-regulation of neuronal injury, glial activation, vascular endothelial dysfunction, oxidative stress, and inflammatory pathways[20,21]. Consequently, these disorders may not be sufficiently treated by modulating a single pathway.
The secretome of MSCs has drawn considerable interest due to its immunomodulatory, anti-inflammatory, trophic, anti-apoptotic, regenerative, and angiogenic properties. It secretes diverse soluble mediators and growth factors, includ
Stem cell-derived secretomes and EVs can be obtained from a wide range of cellular sources. For MSC-based products, the most commonly investigated sources include bone marrow, adipose tissue, umbilical cord, Wharton’s jelly, and other perinatal tissues. Cellular sources of particular interest in retinal research also include embryonic stem cells, induced pluripotent stem cells (iPSCs), neural progenitor cells, retinal progenitor cells, and patient-derived iPSC-derived retinal cells. These sources cannot be considered equivalent, as cellular identity, tissue of origin, donor characteristics, differentiation stage, and culture conditions may all affect EV yield, molecular cargo, biological potency, immunomodulatory activity, and safety[7,8,12,18,19]. For this reason, both the specific cell type and its tissue of origin should be clearly reported when secretome and EV products are evaluated.
Several bioengineering strategies have been explored to optimize stem cell-derived secretome and EVs, including hypoxic culture, inflammatory preconditioning, three-dimensional culture systems, genetic modification of parental cells, cargo loading, and membrane engineering[19,22,23]. These strategies may increase EV yield and enhance their regenerative, neurotrophic, and immunomodulatory properties[22,23]. A high degree of heterogeneity remains a major barrier to the translation of these experimental findings[11]. Stem cell secretome and EVs remain sensitive to manufacturing conditions[19]. Therefore, a lack of standardized isolation, characterization, potency testing, dosing, and reproducibility criteria may limit unbiased comparison across studies[22,23].
The stem cell secretome is highly relevant to retinal diseases because of the unique local microenvironment and its intricate processes involving RPE, ECM components, Müller cells, astrocytes, microglia, photoreceptor, and RGCs[2,7,21]. In degenerative and ischemic retinal disorders, this intricate network may be disrupted following oxidative stress, inflammatory cytokine release, microglial and Müller cell activation, abnormal metabolism, vascular dysfunction or neovascular responses, and progressive neuronal or photoreceptor cell loss[2,21].
Stem cell-derived EVs and soluble secretome factors may target several of these interconnected mechanisms by delivering regulatory proteins and RNAs that modulate inflammatory signaling, apoptosis, oxidative injury, glial responses, RGC survival, photoreceptor preservation, and other tissue repair pathways[7,12,13]. In experimental models of retinal degeneration, EVs derived from neural progenitor cells or MSCs have demonstrated protective effects on photoreceptors[15,16]. These protective effects may be mediated, at least in part, by the modulation of retinal inflammatory responses. In Royal College of Surgeons rats, neural progenitor cell-derived exosomes preserved outer nuclear layer thickness and visual function while delaying photoreceptor degeneration[24]. This experiment also showed their preferential integration with retinal microglia. Likewise, exosomal microRNAs derived from neural progenitor cells were preferentially internalized by retinal microglia; they also exerted anti-inflammatory effects via the suppression of tumor necrosis factor-alpha, interleukin-1β, and cyclooxygenase-2 mediated pathways, thereby inhibiting photoreceptor apoptosis[24].
Similarly, MSC-derived EVs improved retinal structure and function in rd10 mice by reducing microglial, Müller glial, and macrophage activation through a miR-146a/Nr4a3-related anti-inflammatory mechanism[15]. Further evidence from toxin-induced and genetic disease models of retinal degeneration identified MSC-derived exosomal miR-21 as an important mediator of photoreceptor protection, acting through the reduction of apoptotic injury[16]. In optic nerve crush models, intravitreal MSC-derived exosomes improved RGC survival, decreased inflammatory cytokine expression, attenuated apoptosis, and activated phosphatidyl-inositol-3-kinase (PI3K)/AKT signaling; suggesting potential benefits in traumatic- and glaucoma-related neurodegeneration[25]. Taken together, these findings support secretome- and EV-based therapies as multifactorial strategies that modulate inflammatory, apoptotic, neurotrophic, and vascular pathways, rather than acting on a single molecular target[7,12,13].
The stem cell secretome may also contribute to regulating retinal immune and inflammatory responses, which are increasingly recognized as important contributors to degenerative and ischemic retinal damage. Although the retina is protected by specialized barriers and local immune-regulatory mechanisms, chronic oxidative stress, metabolic injury, aging, and inherited degeneration can activate microglia, Müller cells, astrocytes, and infiltrating immune cells, generating a pro-inflammatory milieu that accelerates neuronal and photoreceptor loss[12,21]. EVs released from retinal cells may support retinal homeostasis; although they have been found to enhance pathophysiologic responses in diseased conditions[21]. These findings frame EVs as both contributors to retinal pathophysiology and potential therapeutic tools. For this reason, translation of secretome- and EV-based approaches to the bedside will demand thorough specification of their source, cargo, potency in line with real-world standardizations; as well as specific disease contexts for application of this technology[11,21].
The concept of tailored secretomes and engineered EV-based products further expands the therapeutic scope of acellular regenerative medicine. Preconditioning of parental MSCs via hypoxia, three-dimensional culture, cytokine exposure, and other biochemical or physical cues, may modify vesicle yield and cargo composition[23]. On the other hand, proteins, small molecules, or genetic material can be added or modified to enhance their delivery and targeted effects[23]. Pre-clinical findings supported the premise that MSC-derived exosomes loaded with microRNA-205 can antagonize intraocular (posterior segment) neovascularization, as well as vascular leakage and endothelial proliferation via the concurrent inhibition of VEGF-A & angiopoietin 2 (ANGPT2) receptors[26]. This finding underlines the promise of such regenerative approaches in ameliorating DR, retinopathy of prematurity (ROP), neovascular AMD (nAMD); and other retinal disorders marked by a course of increased vascular permeability with eventual angiogenesis[26,27]. Nevertheless, translation will require resolution of major barriers, including scalable production, purification, EV nomenclature, characterization, cargo consistency, potency assays, biodistribution, long-term safety, regulatory classification, and reproducible quality-control standards[11,23,27]. The secretome generated from stem cells has many bioactive constituents that jointly affect retinal homeostasis and disease processes; these are outlined in Table 1.
| 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] |
A growing body of preclinical evidence supports the therapeutic potential of stem cell-derived secretomes and EVs in retinal disease, with effects reported across models of retinal degeneration, DR, glaucoma, optic nerve injury, uveitis, and retinal vascular disease[2,7,12,13].
Preclinical studies of stem cell secretome- and EV-based approaches have reported neuroprotective effects in several experimental models of retinal damage, owing to these approaches’ capacity to modulate multiple pathophysiological mechanisms. Degenerative retinal diseases are established via complex processes involving retinal support cells, e.g., astrocytes, Müller cells, etcetera; as well as ECM components, RPE, photoreceptor and RGCs[2,7,21]. Retinal degenerative disorders are characterized by disease-dependent interference with retinal homeostasis and neurophysiology. These disruptions are often mediated by oxidative stress, glial cell activation, ischemia, neuronal apoptosis, and the release of pro-inflammatory cytokines[2,21]. Acellular (secretome and EV-based) regenerative approaches bear protein, lipid, mRNA, and microRNA cargoes that may modulate multiple disease signaling pathways simultaneously.
In preclinical models of retinal and optic nerve disease, stem cell-derived EVs have been associated with reduced inflammatory signaling, attenuation of oxidative injury, enhanced RGC survival, photoreceptor preservation, and partial restoration of the retinal microenvironment[7,12,13]. Other experimental findings indicated that MSC-derived secretomes offer neuroprotection via paracrine signaling without direct retinal cell internalization. Experiments performed on in vitro porcine retinal degeneration models revealed that human bone marrow-derived MSC secretomes preserved retinal morphology by modulating biochemical pathways linked with oxidative stress, autophagy, apoptosis, and necroptosis[28]. These findings are relevant to degenerative retinal disorders like RP, DR, glaucoma-associated RGC attenuation, ischemic retinopathies and optic neuropathies; particularly those potentiated by increased oxidative stress, glial activation, vascular dysfunction, neuro-inflammation, and apoptosis[2,7,12,21,28]. These factors offer further justification for the exploration of acellular regenerative therapies in relation to retinal diseases[7,12,28].
Experimental studies of secretome- and EV-based retinal therapies have shown that neuroinflammation may be suppressed through modulation of microglial and Müller cell responses. In degenerative and retinal vascular diseases, sustained activation of local immune and glial cells contributes to cytokine release, oxidative damage, ECM remodeling, vascular dysfunction, and secondary injury to neurons and photoreceptors[2,21]. EVs may modulate these processes by delivering regulatory microRNAs, proteins, and other signaling molecules to target retinal cells, dampening inflammatory pathways and favoring a less harmful retinal microenvironment[12,15,24]. In rd10 mice, MSC-derived EVs reduced microglial, Müller cell, and macrophage activation, inhibited nuclear factor kappa B signaling, lowered pro-inflammatory cytokine expression, and upregulated anti-inflammatory cytokines via miR-146a/Nr4a3[15]. However, in our opinion, EVs should not be considered uniformly protective. In DR models, bone marrow MSC exosomes (let-7b-5p) limited hyperglycemia-induced microglial activation, cytokine expression, retinal apoptosis, and tissue injury by inhibiting Toll-like receptor 4/activating transcription factor 4[29]. These findings emphasize the contribution of inflammation to retinal disease progression, reiterating its relevance as a therapeutic target in degenerative and retinal vascular disorders[2,21].
Beyond immunomodulation, secretome- and EV-based interventions may support photoreceptor and RGC survival by influencing neurotrophic, anti-apoptotic, and antioxidant effects[7,12,13,28]. In optic nerve crush models, intravitreal administration of MSC-derived exosomes increased RGC survival, activated PI3K/AKT, and reduced inflammatory cytokine expression[25]. Studies involving viable MSC administration have also reported retinal protective effects in experimental models, including DR[30], RP[31], and neurotrauma-associated retinal degeneration[32]. These studies, however, involved cell-based interventions rather than isolated secretome or EV preparations and therefore provide only indirect support for paracrine mechanisms, not direct evidence of acellular therapeutic efficacy. Despite these promising findings, the supporting evidence on secretome- and EV-based therapies remains predominantly preclinical and requires further translational research and disease-specific validation.
Acellular regenerative platforms may also positively influence vascular dysregulation and pathologic angiogenesis, particularly in retinal disorders associated with ischemia, inflammation, altered vascular permeability and endothelial dysfunction[2,17,21]. Retinal vascular diseases such as DR, ROP, and nAMD are driven by multifactorial pathophysiologic processes in which VEGF-A & ANGPT2 interact alongside other secondary mediators of inflammation and vascular dysfunction[17,26]. In this context, exosomal non-coding RNAs are increasingly being investigated as potential modulators of vascular distress expression rather than just simple biomarkers[17]. Experimental data suggest that MSC-derived EVs can be enriched or engineered with regulatory RNA cargo to suppress pathological angiogenesis. In models relevant to nAMD, MSC-derived exosomal long non-coding-AGT-3 inhibited endothelial angiogenesis and choroidal neovascularization, with experimental evidence implicating p53 stabilization and downstream anti-angiogenic signaling[33]. These findings support a broader concept of retinal repair in which secretome- and EV-based approaches may act not only on neuronal survival, but also on the vascular and inflammatory microenvironment that contributes to retinal degeneration and visual loss[17,21,26,33].
EVs should not be considered intrinsically protective or intrinsically pathogenic, because their biologic effects depend on the producing cell, its physiological or disease state, cargo composition, recipient cell type, and experimental context. In MERTK-associated RP models, EVs released by patient-derived iPSC-RPE carrying MERTK mutations showed altered RNA and protein cargo enriched for inflammatory and immune-regulatory signatures. In vitro and in vivo, these vesicles were taken up by microglia, rapidly increased pro-inflammatory factor expression, and promoted M1 polarization and migration; hence supporting a disease-propagating role of RPE-derived EVs in early retinal inflammation[34]. By contrast, stem cell-derived EVs and engineered EV platforms are being explored as potential therapeutic platforms capable of delivering selected regulatory RNAs or other bioactive molecules simulating anti-inflammatory, anti-apoptotic, and anti-angiogenetic pathways[12,23,26,27,33]. This contrast reinforces the need to define EV-based interventions based on their cellular source, production conditions, isolation method, cargo profile, potency, and disease context, rather than relying solely on their expression of surface markers[11].
Throughout the disease-specific synthesis, evidence is described according to both experimental level and directness. Studies administering isolated conditioned medium, secretome preparations, or EV-based products are considered direct acellular evidence. In vitro/ex vivo, organoid, rodent, and human findings are identified separately. Studies involving transplantation or systemic administration of viable stem or progenitor cells are cited only when they provide mechanistic evidence relevant to paracrine signaling and are not interpreted as direct evidence of therapeutic efficacy for acellular secretome- or EV-based products.
Throughout the disease-specific synthesis, mechanistic pathways are described as causal only when supported by direct perturbation, inhibition, rescue, target-validation, or equivalent mechanistic experiments in the cited study. Where such evidence is unavailable, associations are described using appropriately qualified language such as “associated with”, “implicated in”, or “consistent with”.
In DR, experimental studies indicate that MSC-derived sEVs may attenuate several components of diabetic retinal injury rather than acting on a single pathway. In streptozotocin-induced diabetic rats, intravitreal administration of MSC-derived sEVs reduced oxidative stress and apoptosis, partly through NEDD4 delivery and modulation of the PTEN/AKT/NRF2 axis in retinal pigment epithelial cells[14]. Other strategies based on MSC-derived sEVs attenuated microglial activation, NLRP3 inflammasome signaling, inflammatory cytokine release, and blood-retinal barrier dysfunction through microRNA-mediated mechanisms, including miR-22-3p delivery[35]. Further preclinical studies in DR models reported lower inflammatory mediator expression, reduced VEGF-related anti-angiogenetic activity, decreased glial activity, and preservation of RGCs or retinal structural integrity after MSC-derived EV or exosome treatment[36].
More recently, engineered EV platforms have extended this therapeutic framework. Photoreceptor-targeted USP25-enriched MSC-derived EVs modified with the MH42 peptide improved retinal function and reduced photoreceptor apoptosis in db/db mice by limiting hyperglycemia-induced attachment of ubiquitin to alpha-crystallin[37]. These findings are relevant because DR is increasingly understood as a multifactorial retinal disease involving metabolic stress, endothelial dysfunction, inflammation, glial activation, blood-retinal barrier disruption, neuronal injury, and other retinal traits of cellular dysfunction. The capacity of EVs to transfer proteins and regulatory RNAs to target multiple retinal cell populations supports their further investigation as potential experimental treatment platforms for complex retinal diseases[2,7,12,13].
In inherited retinal diseases such as RP, progressive photoreceptor degeneration is primarily caused by underlying genetic defects; although inflammation, metabolic dysregulation, and apoptosis may further contribute to disease progression[1,15,16]. Retinal morphology and photoreceptor preservation in rd10 mice following intravitreal administration of MSC-derived EVs correlated with electro-retinography findings[15]. Complementary experimental work identified exosomal miR-21 as a mediator of photoreceptor protection through regulation of programmed cell death protein 4[16].
In parallel, engineered photoreceptor-derived EVs conjugated with the MH42 peptide have been used to deliver Cullin 7 small interfering RNA (siRNA) selectively to photoreceptors, thereby attenuating retinal degeneration in MNU-induced and Pde6βrd1/rd1 mouse models, by limiting Cul7-mediated tagging of glutathione peroxidase 4 with ubiquitin and consequent photoreceptor ferroptosis[38]. Patient-derived iPSC retinal organoids provide an additional platform for modelling inherited retinal disease phenotypes so as to screen therapeutic approaches, and study patient-specific retinal biology[18]. Together, these findings suggest that EV and secretome-based strategies may complement gene- and cell-based approaches as adjunctive therapies targeting shared pathways that trigger photoreceptor stress, inflammation, apoptosis, and tissue degeneration, even without resolving preexisting mutations.
AMD has also emerged as an important field for secretome- and EV-based investigation, although the contemporary evidence base still consists mostly of experimental studies. In dry AMD models, MSC-derived exosomes protected RPE cells from oxidative insult, decreased the release of lactate dehydrogenase and reactive oxygen species, and showed increased antioxidant activity. They further limited apoptosis through modulation of the Nrf2/Keap1 pathway and the Bcl-2/Bax balance. In vivo, intravitreal administration of these exosomes attenuated sodium iodate-induced injury involving the RPE, photoreceptor inner and outer segments, and outer nuclear layer, supporting a possible role for MSC exosomes in oxidative stress-driven RPE and outer retinal damage[39].
In neovascular disease models, exosome-based delivery of regulatory noncoding RNAs has provided additional anti-angiogenic evidence. MSC-derived exosomes loaded with miR-205 inhibited vascular endothelial proliferation, hyperpermeability, migration, tube formation, retinal and choroidal neovascularization by targeting VEGF-A and ANGPT2[26]. These findings are relevant to nAMD and other retinal vascular diseases in which hypoxia, VEGF signaling, inflammation, oxidative stress, endothelial dysfunction, and barrier disruption interfere with normal physiology[27]. Complement dysregulation remains relevant to AMD biology; however, the cited iPSC-RPE study[40] does not evaluate a secretome- or EV-based intervention and is retained here only as disease-context evidence. The findings reported from reviewed studies suggest that future EV-based therapies for AMD should be developed with proper consideration for the multifactorial pathogenesis of AMD; taking into account oxidative stress-related RPE dysfunction, complement system dysregulation, angiogenesis, and inflammatory vascular remodeling.
For this review, evidence maturity was classified using a review-specific four-level framework. Most retinal secretome- and EV-based evidence currently falls within levels 1-2. The macular-hole case series represents limited level 3 evidence, whereas no retinal indication currently has level 4 evidence. This framework reflects translational maturity and evidence directness rather than methodological quality and is not a validated clinical grading system.
To permit direct study-level comparison, Table 2 summarizes key original retinal and optic-nerve secretome- and EV-related studies according to experimental model, evidence level, product identity and cellular source, preparation and EV characterization, administration route and dose, comparator, sample size, follow-up, outcome measures, major findings, and principal methodological limitations.
| Ref. | Indication/model and evidence level | Product/source | Preparation and characterization | Route and dose (source-reported metric) | Comparator | Sample size and follow-up | Main endpoints and findings | Major limitations/design reporting |
| Sun et al[14] | Diabetic retinopathy; high-fat diet/STZ Sprague-Dawley rats and high-glucose RPE cells. Level 2; direct acellular evidence | Human umbilical-cord MSC-derived sEVs; NEDD4 identified as bioactive cargo | Conditioned medium; differential centrifugation followed by ultracentrifugation and 0.22-μm filtration. TEM, NTA and western blot; CD9, CD63, HSP70, Alix and TSG101 positive; Calnexin negative; mean diameter 171.3 ± 71.7 nm | Intravitreal; single dose of 1 × 106 particles in 3 μL at 12 weeks after STZ (particle-number dose) | PBS; HFL1-derived sEVs; normal control | Endpoint-dependent: Retinal thickness n = 6/group; biochemical/qPCR analyses n = 3/group. Animals evaluated 20 weeks after STZ, approximately 8 weeks after treatment | Retinal morphology/thickness, apoptosis, oxidative stress, NEDD4/PTEN/AKT/NRF2 signaling. MSC-sEVs reduced oxidative injury and apoptosis | Rodent metabolic model; single administration; relatively small and endpoint-dependent sample sizes; random allocation reported; blinding not clearly reported |
| Zhang et al[15] | Retinitis pigmentosa; rd10 mice, with complementary 661W/BV2 experiments. Level 2; direct acellular evidence | Human umbilical-cord MSC-derived EVs; miR-146a implicated in Nr4a3 regulation | EVs enriched by differential ultracentrifugation. CD63/CD81 characterization and particle-size analysis; 30-200-nm fraction predominated | Intravitreal; 1 × 1010 EVs in 1 μL/eye at P14 and P21 (particle-number dose) | Normal saline; WT mice | Outcome-specific group sizes; optomotor analysis included approximately n = 5-7/group. Functional/morphological assessment at P27-P28 | Optomotor response, ERG, photoreceptor survival, retinal morphology, microglial/Müller-cell/macrophage activation, NF-κB and miR-146a/Nr4a3 signaling. EVs preserved photoreceptors and retinal function | Genetic mouse model; short developmental follow-up; endpoint-dependent sample sizes; no long-term assessment; blinding/randomization not consistently reported |
| Bian et al[24] | Inherited retinal degeneration; Royal College of Surgeons rats. Level 2; direct acellular evidence | Mouse neural progenitor cell-derived exosome preparation | Differential centrifugation plus sucrose-gradient density centrifugation. HSP70, CD63, CD9 and CD81 positive; TEM; NTA; approximately 50-180 nm, mean ~98 nm | Subretinal; 1 μL/eye containing approximately 1.09 × 109 vesicles (particle-number dose) | Vehicle and untreated controls | At least 3 biological samples/experiment; assessments through 28 days | OKR, scotopic ERG, outer nuclear layer preservation, photoreceptor apoptosis and microglial uptake/activation. Functional and structural preservation reported | Small experimental samples; rodent inherited-degeneration model; invasive subretinal delivery; follow-up ≤ 28 days; randomization/blinding incompletely described |
| Cui et al[25] | Optic-nerve crush in rats. Level 2; direct acellular evidence | Rat bone-marrow MSC-derived exosomes | Exosomes isolated from MSC-conditioned medium; TEM and western blot characterization; approximately 93-nm peak size; CD63/TSG101 positive and GM130 negative | Intravitreal; 3 × 109 vesicles in 5 μL, single administration | PBS/vehicle | NR for consolidated total sample size; approximately 30-day follow-up | RGC survival, retinal histology, apoptosis, inflammatory cytokines, Bcl-2/Bax/caspase-3 and PI3K/AKT signaling. Increased RGC survival and reduced inflammatory/apoptotic signaling | Acute traumatic optic-nerve model; sample size not consistently reported across endpoints; single administration; limited follow-up; randomization/blinding not clearly reported |
| Zhang et al[26] | Oxygen-induced retinopathy and laser-induced choroidal neovascularization in mice. Level 2; direct engineered-acellular evidence | Human MSC-derived exosomes engineered with miR-205 | Differential ultracentrifugation; TEM, NTA and western blot; predominantly 100-150 nm; CD63, HSP70 and TSG101 positive. miR-205 loaded by electroporation | Intravitreal; administered at P12 in the OIR model and immediately after laser injury in the CNV model; injected particle-number/volume dose NR | PBS, unloaded exosomes and free miR-205 | Principal in vivo analyses n = 5/group. OIR endpoint P17; CNV endpoint 7 days | Retinal/choroidal neovascularization, Evans-blue leakage, OCT, FFA and VEGFA/ANGPT2 signaling. Exo-miR-205 reduced pathological angiogenesis and leakage | Acute neovascularization models; small groups; very short follow-up; injected vesicle dose not clearly reported; authors noted lack of in vivo confirmation of uptake by retinal endothelial cells |
| Usategui-Martín et al[28] | Spontaneous degeneration of ex vivo porcine neuroretinal explants. Level 1; direct acellular secretome evidence | Human bone-marrow MSC secretome/conditioned co-culture medium; not a purified EV preparation | BMSCs characterized phenotypically; secretome consisted of medium obtained from NR-BMSC co-culture; no fractionation into soluble and EV components | Ex-vivo medium exposure; 0.75 mL conditioned medium plus 0.75 mL culture medium (conditioned-medium volume; not an isolated EV dose) | Fresh NR; monocultured NR; NR co-cultured with viable BMSCs | 8 porcine eyes; 32 explants; n = 8 per experimental condition; 72 hours | Retinal morphology, RGC/photoreceptor markers, TUNEL, apoptosis, necroptosis, autophagy, oxidative-stress and inflammatory gene expression. Secretome attenuated several degeneration-associated changes | Ex vivo rather than in vivo model; short 72-hour exposure; secretome was not fractionated or compositionally standardized; cannot attribute effects specifically to EVs or soluble factors; selected analyses performed by a masked investigator |
| Zhang et al[29] | STZ-induced diabetic retinopathy in C57BL/6 mice and high-glucose microglial experiments. Level 2; direct acellular evidence | Mouse bone-marrow MSC-derived exosomes; let-7b-5p manipulated using agomir/antagomir strategies | BMSC-derived exosome preparation with vesicle morphology assessment; let-7b-5p cargo experimentally manipulated and quantified | Intravitreal; 1 μL of an exosome preparation reported at 5 μg/μL every 3 days for 6 weeks (protein-concentration metric) | Unmodified BMSC-Exo and let-7b-5p-modified exosome groups; control/PBS conditions | 24 mice reported; 6 normal controls and 18 diabetic mice; n = 6 in diabetic treatment groups; 6-week intervention | Retinal histology/apoptosis, microglial activation, inflammatory cytokines and TLR4/ATF4 signaling. let-7b-5p-enriched exosomes reduced inflammatory and retinal injury markers | Single STZ mouse model; frequent repeated intravitreal injections; predominantly histological/molecular endpoints; no long-term post-treatment follow-up. Random allocation and blinded operators/assessors were reported |
| Chen et al[35] | Diabetic retinopathy; high-fat diet/STZ Sprague-Dawley rats plus cellular experiments. Level 2; direct acellular evidence | Human umbilical-cord MSC-derived sEVs carrying miR-22-3p | TEM and NTA; peak size approximately 159 nm and concentration ~2.9 × 1011 particles/mL; CD63, CD81 and TSG101 positive; Calnexin negative | Intravitreal; single dose of 1.5 × 109 sEVs in 5 μL after 12 weeks of diabetes (particle-number dose) | PBS-treated diabetic rats and normal controls | Consolidated animal NR; animals sacrificed 4 weeks after injection | Retinal morphology, blood-retinal-barrier leakage, microglial activation, inflammatory cytokines and NLRP3 inflammasome signaling. sEV-miR-22-3p attenuated inflammatory injury and barrier dysfunction | Rodent DR model; single administration; 4-week follow-up; no clinical functional endpoint; random allocation reported, blinding not clearly stated |
| Sun et al[37] | Diabetic retinal neurodegeneration in db/db mice, with additional STZ/genetic mechanistic experiments. Level 2; direct engineered-acellular evidence | MSC-derived EVs engineered for photoreceptor targeting with MH42 and enriched with USP25 | EVs isolated and characterized by TEM, particle analysis and EV-marker profiling; engineered by cargo enrichment and surface targeting | Intravitreal; 1 μL containing 106, 107, or 108 particles; 107 particles were selected for repeated administration every 4 weeks (particle-number dose) | Unmodified MEVs, MEV-USP25, targeted and scrambled-control preparations, and disease controls | Animal sample size varied by endpoint; several quantified experiments used n = 3/group. Treatment followed to approximately 24 weeks | ERG, retinal morphology, ONL/photoreceptor survival, TUNEL, opsin expression and USP25/CRYAA-related ubiquitination. Targeted USP25 delivery improved structural and functional retinal outcomes | Complex engineered product; mouse models only; multiple comparator constructs and endpoint-specific sample sizes; repeated injections; no clinical validation. Data collection/analysis reported as blinded |
| Guo et al[38] | MNU-induced retinal degeneration and Pde6βrd1/rd1 mice. Level 2; direct engineered-acellular evidence | Photoreceptor-derived EVs (non-stem-cell source) engineered with MH42 targeting peptide and Cul7 siRNA | Ultracentrifugation; TEM/NTA and EV-marker analysis; CD9, CD63, Alix and TSG101 positive; Calnexin negative. siCul7 loaded by electroporation | Intravitreal; 1 μL at 1 × 107 particles/μL (particle-number concentration) | Targeted control-siRNA EVs and non-targeted siCul7-EVs | Sample size reported separately for each experiment/figure; no overall number of mice provided; 2-week follow-up | Photoreceptor targeting, retinal structure/function, Cul7/GPX4 signaling and ferroptosis. Targeted siCul7 delivery reduced photoreceptor degeneration | Non-stem-cell EV source and therefore supportive mainly as an engineered-delivery proof of concept; two mouse models; short 2-week follow-up; endpoint-dependent sample sizes |
| Tang et al[39] | Dry-AMD-related oxidative injury; ARPE-19 cells and NaIO3-induced retinal degeneration in rats. Level 1-2; direct acellular evidence | Adipose-derived MSC exosomes | MSC exosome preparation characterized in the original study; detailed characterization parameters should be interpreted according to the authors’ reported “exosome” terminology | Intravitreal in the in vivo model; exact administered dose NR | Oxidant/NaIO3 controls; mechanistic Nrf2 inhibition with ML385 | Consolidated animal sample size and exact follow-up NR | LDH, ROS, SOD, RPE/photoreceptor morphology, Bcl-2/Bax and Nrf2/Keap1/HO-1 signaling. Exosome pretreatment reduced oxidative retinal damage | Oxidative/toxin model rather than spontaneous human AMD; pre-administration design; exact dose, consolidated sample size, and follow-up NR; no human evidence |
| Zhang et al[41] | Large and long-standing idiopathic macular holes; uncontrolled human case series. Level 3; exploratory human evidence, with a direct acellular MSC-Exo subgroup | Human umbilical-cord MSC-derived exosome preparation; 5/7 patients received MSC-Exos and 2/7 received viable MSCs | MSC-Exos isolated from cultured MSC supernatants using sequential ultracentrifugation | Intravitreal administration following pars plana vitrectomy and internal limiting membrane peeling, with intraocular tamponade; exact MSC-Exo dose NR | No untreated concurrent control; viable-MSC recipients did not constitute a randomized comparator | Seven patients overall; five MSC-Exo recipients and two viable-MSC recipients; exact follow-up NR | Six of seven macular holes closed and BCVA improved in five patients overall. One patient receiving a higher MSC-Exo dose developed an inflammatory reaction. Aggregate outcomes cannot be attributed exclusively to the MSC-Exo subgroup | Very small, uncontrolled, mixed-intervention case series; concomitant PPV, ILM peeling, and tamponade; two patients received viable MSCs; aggregate outcomes prevent attribution of independent efficacy to MSC-Exos; no randomized confirmatory study |
Translation of secretome- and EV-based therapies remains at an early, largely preclinical stage for retinal diseases, although there has been accelerated progress in bioengineering in this regard. Compared with viable stem cell transplan
Despite these advances, several barriers including scalable production, purification, batch-to-batch reproducibility, cargo consistency, biodistribution, optimal routes of delivery, dose selection, toxicity, immunogenicity, long-term safety, and regulatory standardization must be addressed before widespread real-world application of acellular regenerative therapies[11,23,27]. Therefore, retinal secretome- and EV-based therapies require disease-specific validation before they can be considered ready for routine clinical use.
Evidence in retinal disease is limited to a small uncontrolled human case series reported by Zhang et al[41]. Seven patients with large and long-standing idiopathic macular holes underwent vitrectomy and internal limiting membrane peeling; five received intravitreal human umbilical cord MSC-derived exosomes and two received viable MSCs, with intraocular tamponade. Six of seven macular holes closed and best-corrected visual acuity improved in five patients overall, while one patient receiving a higher MSC-derived exosome dose developed an inflammatory reaction. Because outcomes were reported within a mixed-intervention, uncontrolled surgical series, and because vitrectomy, internal limiting membrane peeling, and tamponade were concomitant interventions, the study cannot establish an independent therapeutic effect of MSC-derived EVs[41].
Clinical evidence with EV-based therapeutics is still limited and marked by substantial heterogeneity. A 2024 systematic review and meta-analysis identified 21 interventional reports involving 335 patients treated for oncological, infectious, inflammatory, regenerative, and vascular indications[42]. Most were phase I or other early-phase studies. The pooled incidence of serious adverse events was 0.7% while the overall incidence of adverse events was 4.4%. These estimates, however, should be interpreted with caution because the included studies differed considerably in EV source, engineering approach, isolation and characterization methods, dose definition, administration routes, study design, and adverse-event reporting. Clinical evidence in ophthalmology was particularly sparse. One uncontrolled, single-arm study investigated topical EVs derived from allogeneic umbilical cord MSCs in 14 patients with chronic graft-vs-host disease-associated dry eye and reported improvements in symptoms and tear-film parameters[42].
These preliminary findings are insufficient to establish efficacy or justify routine clinical use. At present, no stem cell secretome- or EV-based product has an established indication in retinal practice. Early retinal trials should therefore prioritize ocular and systemic safety, dose escalation, biodistribution, immunogenicity, product consistency, and complications related to the route of administration. Subsequent randomized controlled studies will require standardized manufacturing, validated potency assays, appropriate comparators, and clinically meaningful structural and functional endpoints[11,42].
Efficient delivery remains a central requirement for the clinical translation of acellular retinal regenerative therapies. Therapies targeting the eye’s posterior segment must reach local anatomic sites in therapeutic doses sufficient to cross the blood-retinal barrier. Hence, topical and systemic routes of delivery only offer restricted retinal bioavailability[43-45]. Intravitreal, subretinal, periocular, and suprachoroidal routes of administration are often considered when high local concentrations are required near retinal tissues[43,44]. Among these routes, intravitreal delivery is most common, although diffusion through the vitreous, varied permeability across retinal membranes, rapid clearance, and unpredic
These routes differ substantially in their translational advantages and limitations. Intravitreal administration provides direct access to the vitreous and high local retinal exposure but remains invasive, may require repeated administration, and does not ensure uniform penetration to outer-retinal targets. Subretinal administration provides highly localized exposure adjacent to photoreceptors and the RPE, but requires a more invasive surgical procedure and treats a restricted retinal area. Systemic administration avoids intraocular injection but is limited by the blood-retinal barrier, systemic biodistribution, and low retinal bioavailability, whereas topical administration is the least invasive but generally provides limited posterior-segment exposure. Biomaterial-assisted approaches, including intravitreal hydrogels, may prolong local retention and reduce administration frequency, although their combination with secretome- or EV-based products remains predominantly preclinical[43-46]. At present, available evidence does not support definitive disease-specific recommendations for EV delivery routes; route selection should therefore be guided by the intended retinal target, required local exposure, invasiveness, and anticipated dosing frequency[43,44].
Exosomes and EVs are potential delivery vehicles because their lipid bilayer protects molecular cargo; thus, enabling the transfer of proteins, lipids, and nucleic acids to target cells through membrane interactions, endocytosis, and other uptake mechanisms[9,10]. Bioengineering approaches may further improve their therapeutic performance by modifying vesicle surface properties, enriching selected cargo, or enhancing tissue tropism[11,23]. Recent experimental studies have shown that engineered EVs can be targeted to photoreceptors and used to deliver therapeutic molecules, including USP25 or Cul7-targeting siRNA, with beneficial effects in models of DR and retinal degeneration[37,38]. These data support the feasibility of vesicle-based retinal targeting, but also make clear that biodistribution, intra-retinal penetration, dosing, reproducibility, purity, potency assays, and long-term safety must be defined before these platforms can move toward routine clinical use[11,23,43-45].
Bioengineered EV platforms use the vesicular lipid bilayer as a protective nanocarrier while altering molecular cargo or the vesicle surface to improve stability, retinal cell targeting, cellular reuptake, and disease-specific biological activity. These engineering processes can be performed upstream by modifying the parental cells before vesicle release; or downstream after EV isolation. Common upstream strategies include hypoxic or inflammatory preconditioning, three-dimensional culture, and genetic or transfection-based modification of parental cells. Downstream approaches include passive cargo loading, electroporation, sonication, chemical conjugation, peptide- or ligand-mediated surface functionalization, and hybridization with liposomes or nanoparticles[22,23,27]. These production processes can serve to enrich EVs with microRNA, siRNA, proteins, peptides, or small molecules; and may also redirect them toward selected retinal cell populations[23,27,37,38]. As an example, exosome-mediated delivery of miR-205 was shown to improve vascular barrier function via VEGF-A and ANGPT2 blockade, consequently suppressing retinal and choroidal neovascularization[26]. These potential advantages, however, must be balanced against the possibility that engineering may alter vesicle size, surface charge, membrane integrity, endogenous cargo composition, cellular uptake, biodistribution, immunogenicity, and overall biological potency. Engineered EVs should therefore not be assumed to retain the same properties as their native counterparts and require product-specific physicochemical characterization, validated functional potency assays, and dedicated safety testing[11,23,27].
Similarly, photoreceptor-directed EVs have been used to deliver USP25 or Cul7 siRNA to outer retinal cells, with reported protection against diabetic photoreceptor injury and experimental retinal degeneration[37,38]. Overall, these findings frame bioengineered EVs as flexible delivery platforms for retinal therapy, while underscoring the need for reproducible targeting, controlled cargo loading, scalable production, and rigorous safety validation before clinical translation[23,27,37,38]. Alongside direct exosome engineering, advancements in pharmaceutical technology are providing complementary strategies for the sustained delivery of retinal therapeutics. Regenerative retinal therapies must overcome delivery barriers due to complex pharmacokinetics, and the burden of repeated intravitreal administration; long-acting implants, microparticles, nanoparticles, liposomal carriers, and intravitreal hydrogels have also been investigated as potential technologies to improve intraocular bioavailability[44-46].
Hydrogels are particularly attractive as slow-release intraocular scaffolds that retain therapeutic payloads within the vitreous cavity and release them over extended periods. Their direct combination with secretome-derived products or EVs remains largely preclinical and requires further disease-specific validation[46]. Patient-derived iPSC retinal organoids may support secretome- and EV-based therapeutic development as disease-relevant platforms for mechanistic testing and therapeutic screening[18].
Notwithstanding these advances in targeted therapies and delivery technology, bioengineered secretome and EV-based retinal therapies remain far from routine clinical use. Key unresolved issues include EV heterogeneity, source-dependent cargo variability, methods of separation from non-vesicular contaminants, standardized characterization, storage, and reproducible attribution of biological activity[11]. Data from clinical trials of human stem cell-derived EV suggest an overall favorable safety profile, but interpretation remains limited by heterogeneous manufacturing methods, study designs, EV characterization, and adverse-event reporting, underscoring the need for harmonized standards[42]. In retinal applications, translation is further complicated by ocular barriers, intricate posterior segment pharmacokinetics, route-specific delivery constraints, and the need to achieve adequate tissue exposure while minimizing inflammatory, immunogenic, or off-target effects[43-46].
Engineering strategies, including surface functionalization, cargo loading, and hybrid vesicle systems, may improve targeting and durability, but require rigorous validation to establish potency, dosing, long-term safety, and regulatory classification[23,27]. To summarize these translational requirements, Figure 2 presents a proposed conceptual framework for the development of bioengineered EV-based retinal therapeutics; it is not intended to represent a validated clinical development pathway.
The increasing interest in stem cell secretome- and EV-based therapeutics reflects a broader transition in retinal regenerative medicine from direct cell replacement toward acellular modulation of the retinal microenvironment in diseased states. Stem cell transplantation remains a relevant strategy, particularly when replacement of RPE and/or photoreceptor cells is desired. Experimental evidence indicates that several protective effects attributed to stem cells may also be mediated by paracrine activity rather than stable engraftment, differentiation, or long-term integration of donor cells. This distinction is especially important in retinal disease, where tissue damage usually results from interacting mechanisms, including photoreceptor or RPE dysfunction, oxidative and metabolic stress, inflammatory activation, glial reactivity, vascular instability, and progressive neuronal apoptosis[3,7,12,13].
Secretome- and EV-based approaches are therefore attractive because they may influence multiple pathological processes within the same therapeutic window. Bioengineered EVs and RNA-loaded exosome systems suggest that these products may also be developed as adaptable biological delivery platforms capable of transporting selected molecular cargo to disease-relevant retinal cells[47]. Another potential advantage of this paradigm is that acellular products may offer a more controllable alternative to viable cell transplantation. Exosomes also possess properties that support their use as therapeutic carriers. These biochemical properties include nanoscale dimensions, lipid-bilayer protection of molecular cargo, relative biological stability, low immunogenicity, and the ability to interact with recipient-cell membranes and transfer regulatory proteins, RNAs, lipids, and other bioactive molecules. In our view, these advantages do not eliminate the need for rigorous quality control before clinical translation can be considered[48].
Significant heterogeneity exists between preclinical research methodologies; this restricts comparison between studies and thus hinders the development of standardized protocols. Variability can also be found across studies in terms of stem cell source, donor characteristics, passage number, culture medium, oxygen tension, cellular preconditioning, and the use of conventional or three-dimensional culture systems. Further heterogeneity arises from EV isolation and purification methods, storage conditions, particle characterization, cargo profiling, dose normalization, route and schedule of administration, experimental model, follow-up duration, and the structural or functional endpoints used for evaluation[11,19,22,23,42,49-51]. The term “secretome” is also used inconsistently and may refer to biologically distinct preparations, including unprocessed conditioned medium, soluble-factor fractions, EV-enriched products, purified EVs, and engineered vesicle systems. These preparations are not equivalent, as they may differ substantially in molecular composition, purity, biodistribution, biological potency, and mechanism of action. Meaningful comparison across studies therefore requires standardized reporting of the cellular source, production conditions, isolation and purification methods, EV identity and purity, administered dose, route of delivery, and biological potency. The emergence of consensus characterization standards, good manufacturing practice (GMP)-compatible manufacturing protocols, and product-specific potency assays will be necessary to improve reproducibility and support future clinical translation[11,42,49-51]. From a product-development perspective, clinical translation requires control of the entire manufacturing process rather than characterization of EV number alone. Donor and cell-source selection, passage and culture conditions, scalable production, isolation and purification, storage conditions, and batch-to-batch consistency should be incorporated into GMP-compatible workflows with predefined release criteria for product identity, purity, stability, and biological potency[11,49-51]. For retinal applications, these manufacturing requirements must be integrated with dose-exposure studies assessing route-specific biodistribution, ocular pharmacokinetics, persistence, immunogenicity, and long-term ocular and systemic safety[42-45].
Practical implementation will also depend on manufacturing and healthcare-setting capacity. GMP-grade cell banking, EV production, purification, release testing, storage, and transport are resource-intensive and may favor centralized or specialized manufacturing when local GMP infrastructure is unavailable[49-51]. Route-specific treatment burden is equally relevant. Intravitreal delivery is familiar to retinal practice but remains invasive and may require repeated administration; subretinal delivery requires vitreoretinal surgery and provides localized exposure; suprachoroidal administration requires route-specific devices and expertise; and systemic or topical administration is less invasive but currently provides less predictable posterior-segment exposure[43-46]. Consequently, implementation outside specialized retinal centers may be more challenging, and future development should consider manufacturing access, administration burden, monitoring requirements, storage and logistics, and scalability alongside biological efficacy.
A further limitation is the intrinsic complexity of EV biology. Vesicle composition and function are influenced by cellular origin, donor-cell state, culture environment, priming strategy, purification method, storage conditions, and analytical platform. Consequently, reproducibility, cargo characterization, potency assays, and batch-to-batch consistency are not merely technical requirements, but central determinants of clinical applicability[50,51]. This is especially relevant in retinal disease, where small differences in inflammatory, angiogenic, neuroprotective, or immune-regulatory signaling may have meaningful effects on retinal structure and function. It is also important to emphasize that EVs are not inherently reparative. Their biological effects depend on their source, cargo, and pathological context[34]. These factors are interdependent: The disease-specific retinal microenvironment may influence the biological response to a given preparation, whereas differences in source cells and donor state can alter cargo composition and potency[19,34]. Consequently, compositional complexity and source-dependent variability must be considered together with biosafety, because the acellular nature of a product does not by itself guarantee uniform biological activity or safety across different retinal contexts[11,42]. Similarly, disease-associated EV signatures in Usher syndrome indicate that vesicles may reflect retinal molecular alterations and may serve as non-invasive biomarkers; while also highlighting their affinity for disease-specific cellular stress and remodeling processes[52]. In our view, these findings further emphasize the need for rigorous functional characterization of EV therapies for better identification of non-beneficial subtypes.
Interpretation is also constrained by preclinical study design. Reporting of randomization, blinded outcome assessment, sample-size justification, and longer-term follow-up was variable across the original studies, and publication bias toward positive experimental findings cannot be excluded. Because this narrative review did not apply a formal risk-of-bias instrument, these methodological features are reported qualitatively at study level in Table 2 where available rather than being converted into a quantitative risk-of-bias score.
Current preclinical evidence should, at best, be interpreted as indicating short-term structural protection from acellular treatment approaches. Although numerous experimental studies have reported beneficial effects such as reduced apoptosis, preservation of retinal thickness, and maintenance of photoreceptor layers; none of these outcomes can be relied on as proof of long-term restoration of neuroretinal circuitry and visual function. This distinction is particularly important in inherited retinal degenerations. Secretome or EV-based interventions may help modulate biochemically-mediated disease worsening pathways; but they cannot correct underlying genetic defects that account for photoreceptor damage. Considering these limitations, we therefore suggest that acellular approaches should not be viewed as substitutes for gene-specific correction or cell-replacement strategies in advanced stages of inherited retinal disease[1,3,4].
Given current evidence, secretome- and EV-based interventions should be considered investigational disease-modifying or adjunctive therapies rather than restorative treatments. An earlier stage of disease may have a stronger biological rationale when viable retinal cells are available to respond to anti-inflammatory, neurotrophic, anti-apoptotic, or vascular stabilizing signals. Comparative clinical evidence to support recommendation by disease stage is currently lacking. The preclinical evidence in RP and non-exudative AMD indicates the need for further evaluation of this hypothesis but does not identify a preferred clinical indication or treatment stage[14-16,39]. For future studies, it is important to determine the response variability according to disease stage, residual viable retinal tissue, predominant pathogenic mechanism, delivery feasibility, and safety.
Secretome and EV-based therapies have numerous conceptual and practical benefits compared to conventional cell-based methods; nonetheless, significant limitations persist, as outlined in Table 3. Also, a concise comparison between the scope of the present review and recent relevant reviews is provided in Table 4. Table 5 summarizes the review-specific four-level framework used to classify the translational maturity of retinal secretome- and EV-based evidence. Table 6 summarizes disease-specific direct and supportive evidence, together with the highest translational maturity reached for each retinal or optic-nerve application.
| 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] |
| Ref. | Scope | Primary emphasis | Main distinction from the present review |
| Manai et al[2] | EVs in degenerative retinal diseases | Retinal EV biology, pathophysiology, biomarkers, and therapeutic potential | The present review additionally separates soluble secretome, native EV, exosome-enriched, and engineered-EV product classes and links study-level heterogeneity to translational maturity |
| Yang and Peng[12] | Human stem-cell-derived EVs in retinal repair and regeneration | Molecular mechanisms and regenerative potential | The present review additionally emphasizes product taxonomy, direct vs indirect evidence, study-level methodological comparison, and translational readiness |
| Tseng et al[13] | Cell-free EV therapy across ocular diseases | Broad ocular applications, cellular sources, preclinical evidence, and clinical translation | The present review provides a retina/optic-nerve-focused synthesis with detailed study-level evidence mapping and an explicit evidence-maturity framework |
| Guan et al[27] | Engineered exosome therapies for ocular vascular disease | EV engineering, targeting, and ocular neovascular disease | The present review includes non-engineered secretome/EV products and both neurodegenerative and vascular retinal disorders in addition to engineered platforms |
| Present review | Stem-cell secretome- and EV-based therapies in retinal and optic-nerve disorders | Product classes, disease-specific evidence, delivery, manufacturing, quality control, and translation | Integrates evidence directness, product-class distinctions, study-level heterogeneity, evidence maturity, and disease-by-product mapping within a single retinal-focused framework |
| Level | Evidence category | Interpretation in this review | Principal limitations |
| Level 1 | In-vitro, ex-vivo, or organoid mechanistic evidence | Biological plausibility and mechanistic proof-of-concept | Does not establish in-vivo exposure, biodistribution, safety, or therapeutic efficacy |
| Level 2 | In-vivo animal efficacy evidence | Preclinical proof-of-concept in an intact biological system | Species/model differences, heterogeneous products and doses, and limited prediction of human efficacy |
| Level 3 | Early uncontrolled human feasibility or safety evidence | Preliminary human feasibility, safety, or efficacy signal | Small samples, lack of concurrent controls, confounding/co-interventions, and inability to establish efficacy |
| Level 4 | Controlled human clinical efficacy evidence | Comparative clinical evidence capable of testing efficacy | Requires adequate power, standardized products, appropriate controls, clinically meaningful endpoints, and external validity |
| 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 |
Progress in this field will require stronger biological characterization, improved engineering, and rigorous translational frameworks. Active components within secretomes need to be identified, their mechanisms of action should be defined in disease-specific models, and the influence of disease stage on treatment response must be clarified. At the same time, EV production, purification, cargo loading, retinal targeting, storage, and potency assays need to become more reproducible. Patient-derived iPSC models and retinal organoids may support disease-relevant mechanistic testing and screening of secretome- and EV-based candidates[18].
Future retinal EV trials should prospectively report both product-level and clinically meaningful outcome measures. At minimum, reports should specify donor and cellular source, culture and preconditioning conditions, isolation and purification procedures, EV characterization, batch-release and potency criteria, dose normalization, route and schedule of administration, and concomitant ocular procedures. Clinical studies should prespecify best-corrected visual acuity, optical coherence tomography-based structural outcomes, disease-appropriate functional testing such as electroretinography or microperimetry where relevant, ocular and systemic adverse events, rescue treatment, and follow-up of sufficient duration to distinguish transient biological effects from durable clinical benefit.
Overall, stem cell secretome- and EV-based therapies should not yet be viewed as definitive regenerative solutions for retinal degeneration. Their value is more likely to lie in expanding the therapeutic space between conventional pharmacology and complex regenerative interventions. In the future, these approaches may be combined with gene therapy, anti-VEGF therapy, biomaterial scaffolds, or cell replacement; rather than replacing those aforementioned treatment options. If standardization, safety, potency, and delivery challenges are addressed, acellular strategies may be an important adjunctive platform for preserving retinal morphology and physiology in retinal disorders.
Stem cell secretome and EVs are acellular strategies that carry significant promise as retinal disease therapies. The metabolic properties of these strategies reflect their potential to modulate pathologic retinal microenvironments without stem cell differentiation. Preclinical research findings have elucidated their neuroprotective, anti-apoptotic, anti-inflammatory, and vascular-stabilizing properties in experimental models of RP, DR, AMD, ischemic retinopathy, and optic nerve disorders. Successful clinical translation will require appropriate standardization of products, purification procedures, validated potency assays, dosing, delivery strategies, as well as biodistribution studies; these measures will enhance the reproducibility of manufacturing techniques and subsequent evaluation of long-term therapeutic safety. Consequently, stem cell secretome-based therapeutic approaches should not be viewed as alternatives to proven gene, pharmacologic or stem cell therapies; but rather as disease-modifying adjunctive treatments.
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