This review examines how exosome-associated microRNAs and long noncoding RNAs regulate macrophage polarization and inflammatory–angiogenic signaling in age-related macular degeneration, highlighting their diagnostic and therapeutic potential.
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Review Article
This review examines how exosome-associated microRNAs and long noncoding RNAs regulate macrophage polarization and inflammatory–angiogenic signaling in age-related macular degeneration, highlighting their diagnostic and therapeutic potential.
Age-related macular degeneration (AMD) is a progressive and multifactorial retinal disease that represents a leading cause of irreversible vision loss among the elderly. Increasing evidence suggests that exosomes, small extracellular vesicles that mediate intercellular communication, play a critical role in regulating immune and angiogenic signaling in the retina. These vesicles transport diverse molecular cargo, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Recent studies highlight the importance of exosome-mediated ncRNA signaling in macrophage polarization, a key immunological process involved in AMD progression. Exosomal miRNAs and lncRNAs released from retinal pigment epithelium (RPE) cells, endothelial cells, and immune cells can regulate macrophage phenotypes and alter inflammatory and angiogenic pathways within the retina. Dysregulated ncRNAs, including miR-21, miR-23a, miR-150, and the lncRNA NEAT1, have been implicated in promoting macrophage-driven inflammation, lipid dysregulation, and pathological neovascularization. Through these mechanisms, exosomal ncRNAs contribute to the transition from early retinal stress and drusen formation to advanced forms of AMD characterized by geographic atrophy or choroidal neovascularization. In addition to their mechanistic role in disease progression, exosomal ncRNAs show promise as minimally invasive biomarkers for early diagnosis and monitoring of AMD. Their stability in biological fluids, such as plasma, aqueous humor, and vitreous fluid, suggests their potential use in liquid biopsy approaches. Moreover, engineered exosomes carrying therapeutic ncRNAs represent a promising strategy for modulating macrophage polarization and restoring retinal immune homeostasis. This review integrates current knowledge on the exosome–ncRNA–macrophage axis in AMD, highlighting its role in retinal immune regulation, disease progression, and therapeutic development. Understanding this emerging signaling network may provide new opportunities to develop precision diagnostic tools and targeted therapies to prevent or slow retinal degeneration in AMD.
Age-related macular degeneration (AMD) is one of the most common causes of irreversible vision loss, particularly among older adults. It is a retinal disorder that primarily affects the macula, the central region of the retina responsible for color perception, detailed central vision, and fine visual tasks1. AMD is characterized by progressive degeneration of the macula, which is essential for high-resolution vision. In its advanced stages, the disease manifests in two major forms: geographic atrophy (dry AMD) and neovascular (wet) AMD, the latter involving choroidal neovascularization (CNV)2.
Multiple pathobiological mechanisms contribute to AMD development, including oxidative stress, chronic inflammation, abnormal angiogenesis, and dysregulation of lipid metabolism and the complement system. In recent years, increasing attention has been given to the role of immune cells, particularly macrophages and microglia, and their interactions with retinal pigment epithelium (RPE) cells in AMD pathogenesis3. Macrophages exhibit functional plasticity and can polarize into distinct phenotypes in response to microenvironmental signals. These phenotypes are broadly categorized as M1 (classically activated) and M2 (alternatively activated) macrophages. M1 macrophages are typically induced by stimuli such as interferon-γ (IFN-γ), lipopolysaccharide (LPS), and tumor necrosis factor-α (TNF-α). They produce pro-inflammatory cytokines—including interleukin-1β (IL-1β), interleukin-12 (IL-12), and TNF-α—as well as reactive oxygen species (ROS), thereby promoting pathogen clearance but also contributing to tissue damage4.
In contrast, M2 macrophages are induced by cytokines such as interleukin-4 (IL-4), interleukin-13 (IL-13), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β). These cells produce anti-inflammatory mediators and play roles in tissue repair, angiogenesis, extracellular matrix remodeling, and immune regulation. Although the M1/M2 terminology is useful for organizing macrophage biology, it represents a simplified model and should not be interpreted as a strict binary classification in AMD. Retinal macrophages, resident microglia, and infiltrating monocyte-derived macrophages can occupy mixed, transitional, or disease-stage-specific immune states. Their phenotype is shaped by retinal location, aging, oxidative stress, mitochondrial dysfunction, lipid accumulation, complement activation, hypoxia, drusen-associated inflammation, choroidal neovascularization, and exposure to anti-VEGF therapy. Therefore, M1-like and M2-like labels are used in this review as descriptive functional categories rather than fixed cellular identities. In AMD, inflammatory, angiogenic, reparative, and degenerative macrophage programs may overlap, and the same cell population may contribute to tissue repair in one context while promoting chronic inflammation or pathological angiogenesis in another.
Dysregulated macrophage activity and infiltration in the retina may contribute to several pathological features of AMD, including drusen formation, RPE degeneration, neovascularization, and disease progression. For instance, aged macrophages demonstrate altered lipid metabolism, increased expression of pro-angiogenic genes, and impaired cellular homeostasis, which may accelerate AMD pathology5. Macrophage polarization is particularly relevant in AMD because the aging retina and choroid are exposed to chronic low-grade inflammation (often termed 'inflammaging'), as well as oxidative stress and lipid accumulation. These conditions can shift macrophage behavior toward dysfunctional phenotypes that exacerbate retinal damage6. For example, studies on microRNA-150 (miR-150) have shown that aged macrophages exhibit increased miR-150 expression, which disrupts lipid metabolism and enhances pro-angiogenic gene expression. This mechanism links macrophage dysfunction to AMD pathogenesis, as summarized in Table 1. Mechanistically, the available evidence supports an integrated model in which aging-related retinal stress alters exosome-mediated communication between RPE cells, endothelial cells, microglia, and infiltrating macrophages. Oxidative stress, lipid accumulation, mitochondrial dysfunction, complement activation, and hypoxia can alter exosomal ncRNA cargo, thereby influencing inflammatory and angiogenic signaling. Within this framework, miRNAs such as miR-150, miR-21, miR-146a, and miR-155, and lncRNAs such as NEAT1, may contribute to macrophage or microglial reprogramming, although the degree of direct AMD-specific validation differs among these molecules. Rather than acting through a single pathway, the exosome–ncRNA–macrophage axis appears to link several AMD-relevant processes, including immune activation, lipid dysregulation, VEGF-related angiogenesis, RPE injury, and retinal degeneration.
Non-coding RNAs (ncRNAs) include several RNA classes that do not encode proteins but regulate gene expression at transcriptional, post-transcriptional, epigenetic, and translational levels. Common ncRNA categories include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), small interfering RNAs (siRNAs), PIWI-interacting RNAs (piRNAs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), and tRNA-derived fragments. Among these, miRNAs and lncRNAs have received the greatest attention in retinal inflammation, macrophage biology, and extracellular vesicle-mediated signaling. MiRNAs are short regulatory RNAs that suppress target messenger RNAs, whereas lncRNAs can regulate gene expression by acting as molecular scaffolds, transcriptional regulators, or competing endogenous RNAs. This review focuses on miRNAs and lncRNAs because current evidence most consistently links these two ncRNA classes with exosome-mediated macrophage polarization, RPE stress responses, angiogenic signaling, and AMD-related immune dysregulation. Other ncRNA classes, including circRNAs and tRNA-derived fragments, are biologically relevant but have comparatively limited direct evidence in the exosome–macrophage–AMD axis and are therefore discussed only where they provide useful contextual support.
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Exosomes as mediators of intercellular communication in the retina
Extracellular vesicles (EVs), particularly small EVs commonly referred to as exosomes (30–150 nm vesicles of endosomal origin), have emerged as important mediators of intercellular communication. These vesicles carry biologically active cargo, including proteins, lipids, messenger RNAs (mRNAs), microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and DNA, enabling them to influence the physiological and pathological behavior of recipient cells. Within the ocular microenvironment and in the context of age-related macular degeneration (AMD), several cell types, including retinal pigment epithelium (RPE) cells, choroidal endothelial cells, infiltrating immune cells (such as macrophages), and glial cells, release exosomes under both physiological and pathological conditions7,8,9,10. These exosomes can mediate communication between retinal cells and immune components, thereby shaping the retinal immune microenvironment. Exosomes derived from stressed or diseased cells may contain pro-inflammatory or pro-angiogenic cargo that can propagate pathological signaling. For example, exosomal cargo can contribute to processes such as drusen formation, complement activation, and choroidal neovascularization (CNV)11. Thus, exosomes provide a mechanistic link between the local retinal microenvironment comprising the RPE, choroid, and Bruch’s membrane and immune cells such as macrophages and microglia. By transferring regulatory RNAs and other molecular signals, exosomes can influence macrophage phenotype and immune responses in the retina12.
AMD should not be considered a single uniform disease entity because geographic atrophy and neovascular AMD show distinct but overlapping pathogenic mechanisms. Geographic atrophy is mainly characterized by progressive RPE degeneration, photoreceptor loss, mitochondrial dysfunction, complement activation, oxidative stress, and chronic low-grade inflammation. In contrast, neovascular AMD is dominated by choroidal neovascularization, VEGF-driven angiogenesis, vascular leakage, and active inflammatory remodeling of the choroid–retina interface. These differences may influence exosome biology and ncRNA profiles. In geographic atrophy, exosomal cargo may more strongly reflect RPE senescence, oxidative injury, mitochondrial stress, and complement-mediated inflammation, whereas in neovascular AMD, exosomal ncRNAs may be more closely linked to endothelial activation, macrophage recruitment, angiogenic signaling, and extracellular matrix remodeling. Macrophage and microglial phenotypes may also differ between these forms, with degenerative, inflammatory, lipid-laden, angiogenic, and repair-associated states varying according to disease stage and lesion type. Therefore, exosomal miRNA and lncRNA signatures should be interpreted in relation to AMD subtype rather than as universal biomarkers for all AMD phenotypes.
Non-coding RNAs (lncRNAs and miRNAs) as emerging regulators of macrophage polarization in AMD
Among the diverse classes of non-coding RNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have emerged as particularly important regulators of immune signaling and macrophage function. These molecules influence inflammatory responses, angiogenesis, oxidative stress pathways, and cellular communication within the retinal microenvironment. Increasing evidence suggests that dysregulated ncRNA expression contributes to macrophage reprogramming and immune imbalance in AMD, making exosome-associated miRNAs and lncRNAs attractive candidates for both biomarker development and therapeutic intervention. Non-coding RNAs, particularly microRNAs (miRNAs, approximately 22 nucleotides in length) and long non-coding RNAs (lncRNAs, longer than 200 nucleotides), have emerged as key regulators of gene expression at transcriptional, post-transcriptional, and epigenetic levels13. These regulatory RNAs play important roles in immune cell differentiation and function, including the modulation of macrophage activation and polarization. MiRNAs can fine-tune macrophage responses by targeting messenger RNAs that encode cytokines, transcription factors, lipid metabolism regulators, and cell-surface receptors involved in immune signaling14. In ocular vascular and immune diseases, including AMD, studies have demonstrated dysregulated miRNA expression associated with macrophage dysfunction. For instance, miR-150 has been reported to be upregulated in aged macrophages and peripheral blood mononuclear cells (PBMCs) from patients with AMD. MiR-150 directly targets stearoyl-CoA desaturase-2 (SCD2), thereby altering macrophage lipid metabolism and promoting a pro-angiogenic phenotype that may contribute to disease progression15.
Recent reviews have further highlighted that non-coding RNAs regulate macrophage homeostasis in ocular vascular disorders, such as AMD, diabetic retinopathy, and retinopathy of prematurity. These regulatory mechanisms involve modulation of macrophage polarization, cytokine secretion, and angiogenic signaling pathways16. Although direct evidence regarding the role of lncRNAs in macrophage polarization specifically in AMD remains limited, emerging studies from other disease models suggest that lncRNAs, such as NEAT1, can regulate the M1/M2 macrophage transition through miRNA-mediated regulatory networks. A summary of non-coding RNAs implicated in AMD-related immune regulation is presented in Table 2. Given these observations, it is plausible that exosome-mediated delivery of lncRNAs and miRNAs represents an important regulatory axis through which the retinal and choroidal microenvironment influences macrophage behavior in AMD. Despite advances in understanding AMD pathogenesis and the clinical success of anti-VEGF therapies, several important knowledge gaps remain. In particular, the interplay between the retinal immune microenvironment, especially macrophages, and non-coding RNA regulation remains insufficiently explored17. A deeper understanding of how exosome-derived lncRNAs and miRNAs influence macrophage phenotypic shifts may lead to the identification of novel biomarkers and therapeutic targets for AMD18. The role of exosomes in AMD pathogenesis is illustrated in Figure 1. In the pathophysiology of AMD, aging-related processes and immune dysregulation converge with altered intercellular communication mediated by exosomes and non-coding RNA signaling networks19. Macrophages, which function at the intersection of immune regulation, lipid metabolism, and angiogenesis, are particularly susceptible to modulation by exosome-carried lncRNAs and miRNAs20.
Macrophage polarization remains a useful framework for understanding immune regulation in AMD; however, accumulating evidence suggests that retinal macrophages and microglia exist along a dynamic functional spectrum rather than within discrete polarization states. Aging, oxidative stress, complement activation, lipid accumulation, and local retinal injury collectively influence macrophage behavior, generating mixed inflammatory, reparative, and angiogenic phenotypes that contribute to disease progression.
This review, therefore, aims to summarize the mechanisms by which exosomes derived from retinal pigment epithelium, choroidal endothelial cells, glial cells, and immune cells influence macrophage polarization in the retinal and choroidal environments. Furthermore, we discuss the emerging roles of lncRNAs and miRNAs in this exosome-mediated regulatory process, with particular emphasis on their relevance to macrophage M1/M2 balance in AMD. Finally, we highlight key challenges and future directions, including the need for standardized methods for exosome isolation from ocular fluids, identification of macrophage-specific exosomal cargo, in vivo validation of ncRNA-mediated mechanisms, and potential clinical translation for AMD management21,22,23.
Methodology
This narrative review summarizes current evidence regarding exosome-mediated non-coding RNA (ncRNA) signaling, macrophage polarization, and age-related macular degeneration (AMD). A structured literature search was conducted across PubMed, Scopus, Web of Science, and Google Scholar for studies published through June 2026. Search terms included combinations of “age-related macular degeneration,” “exosomes,” “extracellular vesicles,” “microRNA,” “miRNA,” “long non-coding RNA,” “lncRNA,” “macrophage polarization,” “microglia,” “retinal pigment epithelium,” “choroidal neovascularization,” “retinal inflammation,” “oxidative stress,” and “angiogenesis.” Boolean operators (AND/OR) were used to refine search results and capture relevant interdisciplinary studies. Additional articles were identified through citation tracking of key publications and recent review papers to ensure comprehensive coverage of the topic.
Relevant original studies, clinical investigations, and high-quality review articles were evaluated according to their relevance to AMD pathogenesis, exosome biology, ncRNA regulation, macrophage polarization, retinal inflammation, angiogenesis, biomarker development, and therapeutic applications. Studies were included if they investigated exosome-mediated signaling in retinal or ocular tissues, examined the role of miRNAs or lncRNAs in macrophage regulation or inflammatory pathways, explored mechanisms relevant to AMD pathogenesis (including oxidative stress, angiogenesis, and immune dysregulation), or provided mechanistic insights into exosomal ncRNA signaling or macrophage polarization. Studies unrelated to ocular diseases or lacking relevance to immune regulation in AMD were excluded.
The selected literature was analyzed to identify key molecular pathways, regulatory ncRNAs, and experimental evidence linking exosomal communication with macrophage-mediated retinal pathology. Particular attention was given to studies describing ncRNA-mediated modulation of macrophage phenotypes (M1/M2), angiogenic signaling pathways, and inflammatory responses within the retinal microenvironment. The findings were organized into thematic sections focusing on exosome biology, ncRNA regulation, macrophage polarization, diagnostic biomarkers, and therapeutic implications. Tables and figures were incorporated to summarize key ncRNAs, exosomal biomarkers, and mechanistic pathways implicated in AMD progression.
Because the aim of this article was to provide a mechanistic and translational narrative synthesis rather than a formal systematic review, formal systematic review procedures, study-level risk-of-bias assessment, evidence grading, and meta-analysis were not performed. The included literature was evaluated thematically according to its relevance to AMD pathogenesis, exosome biology, ncRNA regulation, macrophage or microglial polarization, retinal inflammation, angiogenesis, biomarker development, and therapeutic translation. Evidence was interpreted cautiously, and studies were distinguished according to whether they provided direct AMD evidence, evidence from ocular disease models, or mechanistic evidence extrapolated from non-ocular inflammatory or vascular models.
Exosome-mediated intercellular communication in the pathophysiology of AMD
Figure 2 illustrates exosome-mediated signaling and therapeutic strategies in AMD. Exosomes have emerged as crucial mediators of intercellular communication within the retinal microenvironment, facilitating the exchange of molecular signals between retinal pigment epithelium (RPE) cells, photoreceptors, choroidal endothelial cells, glial cells, and immune cells such as macrophages and microglia23. These nanosized extracellular vesicles (30–150 nm) originate from the endosomal system and are released when multivesicular bodies fuse with the plasma membrane. Exosomes carry diverse molecular cargo, including proteins, lipids, and nucleic acids such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The composition of this cargo often reflects the physiological or pathological state of the parent cell and can modulate gene expression and signaling pathways in recipient cells24. In the context of AMD, exosome-mediated communication has increasingly been recognized as a key mechanism linking inflammation, oxidative stress, lipid accumulation, and choroidal neovascularization (CNV). Under pathological conditions, such as oxidative stress or lipid overload, exosomes in RPE cells can become enriched with pro-angiogenic and pro-inflammatory mediators.
Several limitations must be addressed before exosomal ncRNAs can be considered clinically reliable biomarkers for AMD. Pre-analytical variability can arise from differences in sample source, including plasma, serum, aqueous humor, and vitreous humor, each of which may reflect different biological compartments. Exosome yield and cargo profiles may also vary according to collection method, storage conditions, freeze–thaw cycles, centrifugation protocols, commercial isolation kits, size-exclusion chromatography, ultracentrifugation, and immunoaffinity-based enrichment. Additional challenges include normalization of ncRNA levels, contamination by hemolysis-derived miRNAs, difficulty assigning exosomes to a retinal, immune, endothelial, or systemic cellular origin, small cohort sizes, disease-stage heterogeneity, and limited independent validation. Therefore, exosomal ncRNA signatures should currently be regarded as promising investigational biomarkers rather than clinically ready diagnostic tools. These may include vascular endothelial growth factor (VEGF), complement components (e.g., C3 and C5b-9), and lipofuscin-associated molecules. Such exosomes can promote endothelial cell activation, recruit immune cells, and polarize macrophages toward the M2 phenotype, thereby contributing to CNV formation and disease progression in AMD. Several miRNAs contained within exosomes have been implicated in AMD-associated inflammatory and metabolic pathways. For instance, miR-21, miR-146a, miR-155, and miR-150 have been reported to regulate inflammatory signaling, lipid metabolism, and immune responses, which are central to AMD pathogenesis25,26. Among these, miR-150 has attracted particular attention because it is enriched in exosomes derived from aged macrophages and from peripheral blood mononuclear cells (PBMCs) from patients with AMD. MiR-150 has been shown to modulate genes involved in lipid metabolism and promote a pro-angiogenic macrophage phenotype, thereby linking immune dysregulation to AMD progression. Beyond their mechanistic role in disease development, exosomes also show promise as biomarkers for AMD. Because exosomes can cross biological barriers and reflect pathological changes in retinal tissues, they are attractive candidates for non-invasive diagnostics. Exosomal components can be isolated from biological fluids such as serum, vitreous humor, and aqueous humor, where they may serve as early indicators of retinal stress and immune dysfunction27. Table 3 summarizes selected exosomal biomarkers reported to be relevant to AMD pathogenesis and diagnostic applications. In addition to their diagnostic potential, exosomes have attracted growing interest as therapeutic nanocarriers capable of modulating macrophage polarization and restoring retinal homeostasis. Engineered exosomes can be designed to deliver anti-inflammatory or anti-angiogenic RNA cargo, including specific miRNAs or lncRNAs. Preclinical studies have demonstrated that such approaches can inhibit abnormal angiogenesis, reduce oxidative stress, and rebalance immune cell function in experimental models of AMD28,29,30,31,32,33. Selected exosomal non-coding RNAs with therapeutic and regulatory potential relevant to macrophage polarization and AMD progression are summarized in Table 4. Taken together, exosome-mediated signaling provides a unifying framework linking aging, immune dysregulation, and metabolic stress in AMD. The interplay between exosomal lncRNAs and miRNAs can influence macrophage polarization and thereby shape the retinal microenvironment toward either degeneration or tissue repair34,35,36,37. Understanding this regulatory network may not only improve insights into AMD progression but also facilitate the development of precision-based diagnostic tools and targeted RNA-based exosome therapies. Future research should focus on several critical areas, including standardizing exosome isolation and characterization from ocular fluids, validating ncRNA biomarkers in large clinical cohorts, and optimizing engineered exosome-based delivery systems to enhance therapeutic efficacy and safety38,39,40. Such advances may ultimately support the translation of exosome-based diagnostics and therapeutics into clinical practice for the management of AMD.
This review should be interpreted as a narrative synthesis rather than a systematic review. Formal PRISMA screening, quantitative synthesis, study-level risk-of-bias scoring, and evidence grading were not performed. Instead, the selected studies were organized according to mechanistic relevance, disease context, and translational importance. To avoid overstating the evidence, the discussion distinguishes direct AMD findings from evidence obtained in other ocular disorders, systemic inflammatory models, vascular disease models, or general macrophage biology. This approach allows the review to identify emerging biological themes while acknowledging that several proposed mechanisms require further AMD-specific validation.
Insights into mechanisms for exosomal lncRNA and miRNA networks regulating macrophage polarization in AMD
Recent studies have highlighted the role of exosomes as important carriers of non-coding RNAs (ncRNAs) that regulate gene expression in recipient cells, including macrophages, thereby influencing their functional phenotype39 In the retinal microenvironment, pathological conditions such as increased oxidative stress, lipid dysregulation, and complement activation stimulate the release of altered exosomes from retinal pigment epithelium (RPE) cells and immune cells. These exosomes are frequently enriched with specific ncRNAs that can either promote or suppress macrophage activation pathways40. Mechanistically, exosomal microRNAs (miRNAs) influence macrophage polarization by targeting transcription factors and signaling pathways that determine the balance between the pro-inflammatory M1 phenotype and the pro-angiogenic M2 phenotype. For example, miR-150 transferred through macrophage-derived exosomes has been shown to suppress stearoyl-CoA desaturase-2 (SCD2), resulting in dysregulated lipid metabolism and promoting an angiogenic, M2-like phenotype. This mechanism has been directly associated with the development of neovascular AMD41. Another example involves exosomal miR-21 derived from RPE cells, which can activate the STAT3/VEGF signaling axis, thereby promoting macrophage recruitment and inflammation-driven angiogenesis. In contrast, miR-146a is generally considered an anti-inflammatory miRNA that attenuates NF-κB signaling, suppressing chronic inflammatory responses and limiting retinal tissue damage42. Beyond miRNAs, long non-coding RNAs (lncRNAs) present in exosomes further refine the regulatory network controlling macrophage polarization. LncRNAs can function as competing endogenous RNAs (ceRNAs), molecular scaffolds, or transcriptional regulators. For instance, NEAT1 has been reported to regulate macrophage polarization by sponging miR-148a-3p, thereby influencing the PTEN/PI3K/Akt signaling pathway and promoting a shift toward the M2 phenotype. Additionally, lncRNAs such as HOTAIR and MALAT1 have been implicated in chronic retinal inflammatory conditions, in which altered expression in RPE-derived exosomes may sustain pro-inflammatory responses by modulating NF-κB and STAT1 signaling pathways43,44,45. The complex regulatory network of ncRNAs transmitted through exosomes is summarized in Table 5. These lncRNA-mediated interactions ultimately determine whether macrophages adopt a pro-inflammatory (M1) or pro-angiogenic (M2) phenotype, thereby influencing disease progression in AMD46,47,48,49.
Diagnostic and therapeutic potential of exosomal ncRNAs in AMD
Exosomal ncRNAs have emerged as promising biomarkers and therapeutic targets in AMD. Because exosomes circulate in biological fluids and reflect disease-specific molecular changes, they provide valuable insights into retinal pathological processes. Exosomes can be isolated from minimally invasive sources such as serum, aqueous humor, and vitreous humor, making them accessible tools for disease monitoring and early detection50,51. Several circulating exosomal miRNAs have been associated with AMD severity. For example, elevated levels of miR-21 and miR-150 in circulating exosomes have been correlated with disease progression and inflammatory activation in AMD. Conversely, reduced levels of anti-inflammatory miRNAs such as miR-146a have been linked to enhanced inflammatory responses and worsening retinal pathology52. In addition, exosomal lncRNAs detected in serum may serve as molecular signatures reflecting early immune dysregulation and impending neovascularization. These molecular biomarkers have the potential to complement traditional imaging-based diagnostic techniques by providing dynamic insights into disease activity and treatment response53. The mechanistic overview of exosomal ncRNA-mediated regulation of macrophage polarization in AMD is illustrated in Figure 3. Beyond their diagnostic value, engineered exosomes have gained attention as potential therapeutic delivery systems. Exosomes derived from mesenchymal stem cells (MSCs) or RPE cells can be engineered to deliver anti-inflammatory or anti-angiogenic miRNAs directly to retinal tissues, thereby modulating macrophage polarization and reducing choroidal neovascularization (CNV) in preclinical models54. For example, MSC-derived exosomes enriched with miR-26 or miR-21-5p have demonstrated significant reductions in oxidative stress, VEGF production, and macrophage-mediated angiogenesis in experimental AMD models55,56. Furthermore, advances in exosome engineering, such as surface modification with targeting peptides (e.g., RGD peptides targeting integrin αvβ3 expressed in CNV lesions), have improved delivery specificity to retinal tissues. Collectively, these developments highlight the translational potential of exosome-based diagnostics and therapeutics in AMD. By restoring immune balance and regulating macrophage polarization, exosome-mediated ncRNA delivery strategies may offer novel approaches for halting disease progression. Table 6 summarizes the diagnostic and therapeutic applications of exosomal biomarkers and ncRNAs relevant to AMD progression.
Interplay between exosomes, non-coding RNAs, and macrophage polarization in age-related macular degeneration
The interaction between exosomes, non-coding RNAs (ncRNAs), and macrophage polarization represents an important axis in the immunopathogenesis of age-related macular degeneration (AMD). The retinal and choroidal microenvironments are continuously exposed to chronic oxidative stress, complement activation, and low-grade inflammation, a process commonly referred to as inflammaging57,58,59,60,61. These stressors significantly influence macrophage function and plasticity, shaping their polarization and activity within the retinal tissue.
Exosomes play a central role in mediating intercellular communication within this environment. Acting as molecular messengers, they facilitate crosstalk between retinal pigment epithelium (RPE) cells, choroidal endothelial cells, glial cells, and immune cells such as macrophages and microglia62. Exosomes transport diverse ncRNAs, particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), which can regulate macrophage polarization and consequently influence inflammatory responses, angiogenesis, and tissue remodeling in the retina63. Under physiological conditions, exosomes released by RPE and other retinal cells help maintain immune homeostasis by transferring anti-inflammatory molecules that promote M2-like macrophage polarization. However, within a diseased or stressed retinal environment, the composition of exosomes undergoes substantial changes. Oxidative stress or lipid overload in RPE cells can trigger the release of exosomes enriched with pro-inflammatory and pro-angiogenic ncRNAs, including miR-21, miR-23a, and miR-150, which have been implicated in macrophage dysregulation and altered lipid metabolism63,64,65,66. These altered exosomes may reprogram macrophages toward either a persistent M1-like inflammatory phenotype, contributing to retinal damage and chronic inflammation, or an abnormal M2-like pro-angiogenic phenotype, which promotes choroidal neovascularization (CNV)66. In this manner, exosome-mediated ncRNA signaling can establish a positive feedback loop between stressed or dying RPE cells and activated macrophages, thereby amplifying inflammatory and angiogenic responses in AMD. For instance, RPE-derived exosomes under oxidative stress have been shown to contain miR-21 and miR-23a, which activate angiogenic signaling in macrophages through the PI3K/Akt and STAT3 pathways67. Similarly, aging macrophages exhibit increased expression of miR-150, which disrupts lipid metabolism by inhibiting stearoyl-CoA desaturase-2 (SCD2), leading to a pro-inflammatory and pro-angiogenic phenotype. Furthermore, lncRNAs such as NEAT1 may regulate macrophage polarization through the miR-148a-3p/PTEN signaling axis, influencing both inflammatory and angiogenic responses68. Although the direct role of NEAT1 in AMD has not yet been fully established, similar regulatory mechanisms have been reported in other ocular immune and vascular diseases, suggesting potential relevance to AMD pathology. The non-genetic mechanisms contributing to AMD development in aging individuals are illustrated in Figure 4. Structural and functional deterioration of retinal tissues arises from multiple age-associated processes, including RPE cell senescence, chronic oxidative stress, mitochondrial dysfunction, impaired hemodynamics, lipid accumulation, complement activation, and chronic low-grade inflammation. These factors collectively contribute to RPE degeneration, drusen formation, photoreceptor loss, and choroidal neovascularization, ultimately driving the progression of AMD. Importantly, exosomal ncRNAs not only influence macrophage polarization locally within the retina but can also circulate systemically, reflecting disease state and progression. Altered expression profiles of exosomal miRNAs detected in plasma or aqueous humor of AMD patients have been associated with disease severity and retinal inflammation69. These findings support the emerging concept that exosome-delivered ncRNAs function as intracellular mediators linking aging-related metabolic stress with immune dysregulation and neovascularization in AMD70. Understanding this regulatory network requires precise identification of ncRNA signatures and the cellular sources of exosomes within the retinal microenvironment. Future studies focusing on exosome cargo profiling, functional validation of ncRNAs, and macrophage-specific exosomal signaling pathways will provide deeper insights into AMD pathogenesis71. Ultimately, elucidating this interplay may open new avenues for therapeutic strategies targeting exosomal ncRNA signaling or macrophage polarization pathways.
Emerging diagnostic biomarkers and therapeutic potentials in AMD
The growing understanding of exosome-mediated communication and ncRNA regulation of macrophage polarization has opened new opportunities for identifying diagnostic biomarkers and developing targeted therapeutic strategies for AMD68,69,70,71,72,73. Exosomes are increasingly recognized not only as mediators of intercellular signaling but also as reservoirs of molecular information that reflect the physiological and pathological states of their cells of origin. Because exosomes are stable in biological fluids, including plasma, vitreous humor, and aqueous humor, they are particularly attractive as minimally invasive biomarkers for early diagnosis and monitoring of AMD progression74.
Current clinical application status should be interpreted cautiously. At present, exosomal ncRNAs are not established as routine diagnostic biomarkers or approved therapeutic agents for AMD. Clinical diagnosis, staging, and treatment monitoring still rely primarily on fundus examination, optical coherence tomography, fundus autofluorescence, fluorescein angiography, optical coherence tomography angiography, and visual function assessment. For neovascular AMD, intravitreal anti-VEGF therapy remains the current standard treatment. Exosomal miRNAs and lncRNAs are promising because they may reflect retinal stress, immune activation, angiogenic signaling, or treatment response; however, their use in clinical practice remains investigational. Large independent cohorts, standardized exosome isolation protocols, validated normalization strategies, and prospective studies are still required before exosomal ncRNA signatures can be translated into routine AMD diagnosis, monitoring, or treatment selection.
Exosomal ncRNAs as diagnostic biomarkers
Several studies have reported differential expression of exosomal miRNAs and lncRNAs in patients with AMD compared with healthy individuals. Dysregulated miRNAs such as miR-21, miR-23a, miR-27a-3p, and miR-150 have been detected in both serum and ocular fluids of AMD patients and are associated with inflammatory, angiogenic, and lipid metabolic pathways75. These ncRNAs reflect the molecular reprogramming occurring in macrophages and RPE cells during disease progression.
Importantly, exosomal miRNA signatures may also help distinguish between dry (atrophic) and wet (neovascular) forms of AMD, offering potential for subtype-specific diagnostic profiling76. In addition, emerging evidence suggests that lncRNAs such as NEAT1 and MALAT1, which are often co-packaged with miRNAs in exosomes, may serve as composite biomarkers indicating disease activity or therapeutic response. Selected exosomal ncRNAs and biomarkers associated with AMD are summarized in Table 7.
Therapeutic potential of targeting the exosome–ncRNA–macrophage axis
Exosomes are not only potential biomarkers but also promising therapeutic tools and targets. Modulating exosome biogenesis, release, or cargo composition may reprogram macrophage phenotypes and restore immune homeostasis in the retina77,78,79,80,81,82. For example, inhibition of pro-angiogenic exosome release from RPE cells under oxidative stress or modification of exosomal ncRNA cargo may suppress choroidal neovascularization83.
Alternatively, engineered exosomes derived from stem cells containing anti-inflammatory ncRNAs such as miR-124, miR-146a, or inhibitors of miR-21 have demonstrated the ability to promote beneficial macrophage polarization and reduce angiogenic and inflammatory signaling in preclinical ocular disease models. Exosome-based therapeutics offer several advantages, including intrinsic biocompatibility, low immunogenicity, and natural targeting capabilities, as summarized in Table 8. Despite these promising developments, several challenges remain. These include large-scale exosome isolation, precise loading of therapeutic ncRNAs, and targeted delivery to specific retinal cell populations84,85. Engineered exosome-based ncRNA delivery should currently be viewed as a preclinical concept rather than an AMD therapy approaching routine clinical implementation. Several barriers remain unresolved, including the optimal ocular delivery route, biodistribution after intravitreal or subretinal administration, penetration across retinal layers, selective targeting of macrophages or microglia, dose control, repeated-dosing safety, cargo loading efficiency, batch-to-batch reproducibility, sterility, storage stability, and large-scale manufacturing. Additional concerns include unintended modulation of immune responses, off-target effects in retinal neurons, RPE cells, endothelial cells, or systemic immune cells, and the potential for pro-angiogenic or pro-inflammatory effects depending on exosome source and cargo composition. Regulatory requirements for biologically derived vesicle products are also complex. These challenges must be addressed through standardized preclinical models, toxicology studies, pharmacokinetic analyses, and long-term safety evaluations before engineered exosome therapies can be considered for clinical management of AMD.
The strength of evidence for individual ncRNAs differs substantially. MiR-150 has relatively direct relevance to AMD because altered expression in aged macrophages and AMD-associated immune cells has been linked with lipid metabolic dysregulation and pro-angiogenic macrophage behavior. In contrast, the roles of miR-21, miR-146a, miR-155, and NEAT1 in AMD should be interpreted more cautiously. These molecules have strong mechanistic support in macrophage activation, inflammatory signaling, angiogenesis, and related ocular or systemic inflammatory models, but direct causal validation in AMD tissues, ocular fluids, or AMD-specific macrophage populations remains limited. Therefore, these ncRNAs are considered candidate regulators within the exosome–macrophage–AMD axis rather than fully validated drivers of AMD progression. Advances in exosome engineering, combined with RNA-based therapeutics such as antisense oligonucleotides and miRNA mimics or inhibitors, may pave the way for next-generation treatments that modulate macrophage activity and slow, or even reverse, AMD progression86.
Translational relevance and future perspectives
The growing understanding of exosome-mediated ncRNA signaling has created new opportunities for improving both the diagnosis and treatment of AMD. Exosomal miRNAs and lncRNAs have emerged as promising biomarkers because they reflect retinal stress, immune activation, angiogenic signaling, and disease progression while remaining detectable in minimally invasive biological samples. At the same time, engineered exosomes represent an innovative therapeutic platform capable of delivering regulatory RNA molecules directly to retinal tissues and immune cells.
Despite these advances, significant challenges remain before clinical translation can be achieved. Standardized methods for exosome isolation, characterization, cargo quantification, and biomarker normalization are still needed. Additional studies are required to validate candidate ncRNA biomarkers in large patient cohorts and to determine their reproducibility across different AMD subtypes and disease stages. Similarly, exosome-based therapeutic strategies require further investigation regarding biodistribution, retinal targeting, long-term safety, manufacturing consistency, and regulatory approval.
Future research integrating multi-omics technologies, single-cell transcriptomics, advanced retinal imaging, artificial intelligence-based prediction models, and functional experimental systems will provide a more comprehensive understanding of the exosome–ncRNA–macrophage axis. Such advances may facilitate the development of precision diagnostic tools and targeted therapeutic approaches that can slow or prevent retinal degeneration in AMD.
Recent advances in artificial intelligence combined with multimodal retinal imaging have demonstrated considerable potential for predicting AMD progression and identifying high-risk patients. Integration of molecular biomarkers, including exosomal ncRNA signatures, with AI-assisted imaging analysis may further improve disease stratification, prognostic assessment, and personalized treatment planning in future clinical practice87,88,89,90.
Therapeutic implications and future perspectives
Emerging insights into exosome-mediated communication and ncRNA-driven macrophage polarization in age-related macular degeneration (AMD) have opened new therapeutic avenues beyond conventional anti-VEGF and anti-inflammatory strategies. Due to their nanoscale size, intrinsic biocompatibility, and ability to cross physiological barriers, exosomes are increasingly recognized not only as mediators of disease processes but also as promising therapeutic delivery vehicles91,92,93,94,95,96,97,98,99. The selective sorting of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) into exosomes provides a natural mechanism for targeted molecular delivery. Through this process, exosomes can regulate specific signaling pathways in recipient retinal and immune cells, thereby reshaping the inflammatory and angiogenic microenvironment that drives AMD pathology100. One promising strategy involves engineering exosomes to modulate macrophage polarization by loading them with regulatory ncRNAs. For instance, exosomes enriched with anti-inflammatory or anti-angiogenic miRNAs such as miR-146a, miR-21 inhibitors, or miR-23a mimics may suppress proinflammatory M1 macrophage responses while promoting a reparative M2-like phenotype, thereby restoring retinal immune homeostasis101. Conversely, approaches such as antisense oligonucleotide technology or CRISPR-based gene modulation may be used to inhibit pro-angiogenic ncRNAs, including miR-150, or dysregulated lncRNAs such as NEAT1, which have been implicated in pathological angiogenesis and fibrosis. Representative recent advances and landmark studies in this field are summarized in Table 9. Preclinical studies in ocular and systemic disease models have demonstrated that silencing or restoring specific ncRNAs through exosome-based delivery systems can significantly alter immune cell behavior. These findings highlight the strong translational potential of ncRNA-based therapeutics in AMD. Beyond their therapeutic applications, exosomal ncRNAs also show considerable promise as diagnostic biomarkers for early disease detection and monitoring. Liquid biopsy approaches using plasma, aqueous humor, or vitreous fluid have revealed distinctive exosomal miRNA signatures associated with AMD severity and therapeutic response102. Such molecular biomarkers could be integrated with imaging modalities—including optical coherence tomography (OCT) and fundus autofluorescence, as well as computational modeling approaches to support precision medicine strategies. In this context, patients could be stratified according to their inflammatory or angiogenic molecular profiles, enabling more personalized treatment approaches103. Collectively, these findings, summarized in Table 10, highlight the central role of exosomal ncRNA signaling in regulating macrophage polarization and retinal immune homeostasis, providing a mechanistic basis for the development of innovative diagnostic and therapeutic approaches targeting exosome-mediated pathways in AMD. Despite these promising advances, several challenges remain before exosome-based strategies can be translated into clinical practice. First, standardized methods for exosome isolation, characterization, and quantification are urgently needed to ensure reproducibility across laboratories104,105,106,107. Additionally, a deeper understanding of the mechanisms governing exosomal cargo selection during cellular stress and aging will be critical for the design of effective therapeutic interventions. Ethical and regulatory considerations related to biologically derived exosome therapeutics must also be addressed108,109,110. Future research should focus on mapping the retina-specific exosome interactome and integrating multi-omics approaches, including transcriptomics, proteomics, and lipidomics, to better understand the molecular networks involved in AMD pathogenesis. Advanced experimental systems, such as 3D retinal–macrophage co-culture models and retinal organoids, may provide more physiologically relevant platforms for studying exosome-mediated signaling. Furthermore, integrating nanotechnology with molecular biology could enhance the efficiency of exosome loading, targeting, and delivery.
Together, these advances are expected to transform our understanding of exosome–ncRNA biology in AMD, bridging the gap between mechanistic insights and the development of novel therapeutic strategies for this complex retinal disease110,111,112,113.
Mechanistic integration
Age-related macular degeneration (AMD) arises from a multifactorial convergence of metabolic stress, immune dysregulation, and progressive degeneration of retinal structures. Recent advances in retinal immunobiology have identified exosome-mediated non-coding RNA (ncRNA) signaling as a central mechanism integrating these pathological processes. Exosomes function as nanoscale extracellular vesicles that facilitate the transfer of molecular cargo—including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), proteins, and lipids—between retinal cells and immune cells. Through this intercellular communication system, exosomes coordinate signaling among retinal pigment epithelium (RPE) cells, choroidal endothelial cells, glial cells, and infiltrating immune cells, such as macrophages and microglia, thereby shaping the retina's inflammatory and angiogenic landscape.
Under physiological conditions, exosomes contribute to retinal immune homeostasis. RPE cells and other retinal cells release exosomes that carry regulatory molecules that help maintain balanced macrophage activity and prevent excessive inflammatory responses. These exosomal signals promote controlled macrophage polarization and facilitate tissue repair, debris clearance, and maintenance of the extracellular matrix. In this balanced environment, macrophages can transition between functional phenotypes to support retinal health.
However, aging-related stressors—including oxidative damage, mitochondrial dysfunction, lipid accumulation, impaired choroidal circulation, and complement activation—disrupt this homeostatic communication network. In response to these stress signals, RPE cells and immune cells release exosomes with altered molecular composition. These stress-induced exosomes are often enriched with pro-inflammatory and pro-angiogenic ncRNAs that can reprogram macrophage behavior and amplify pathological signaling within the retinal microenvironment.
Once internalized by macrophages, exosomal ncRNAs modulate gene expression by targeting key transcription factors and signaling pathways involved in macrophage activation and polarization. Several miRNAs have been implicated in this process. For example, miR-21 and miR-23a have been associated with activation of the PI3K/Akt and STAT3 signaling pathways, which promote inflammatory responses and angiogenic activity. Similarly, miR-150 has been shown to disrupt lipid metabolism by inhibiting stearoyl-CoA desaturase-2 (SCD2), thereby promoting a pro-angiogenic macrophage phenotype linked to neovascular AMD.
Long non-coding RNAs further refine this regulatory network. LncRNAs, such as NEAT1, can act as competing endogenous RNAs that sponge specific miRNAs, thereby modulating downstream signaling pathways, such as PTEN/PI3K/Akt. Through these mechanisms, lncRNAs influence macrophage polarization and regulate inflammatory and angiogenic responses within retinal tissues. Although the precise role of several lncRNAs in AMD remains under investigation, accumulating evidence from ocular and vascular disease models suggests that ncRNA-mediated regulatory circuits play a critical role in shaping immune responses in the retina.
Collectively, these processes create a self-amplifying pathogenic loop. Stressed RPE cells release exosomes containing dysregulated ncRNAs, which reprogram macrophages toward pro-inflammatory or pro-angiogenic phenotypes. Activated macrophages, in turn, release additional inflammatory mediators, reactive oxygen species, and angiogenic factors that further damage retinal tissues and stimulate abnormal blood vessel formation. This cycle contributes to key pathological features of AMD, including drusen accumulation, photoreceptor degeneration, extracellular matrix remodeling, and choroidal neovascularization113.
The integration of these mechanisms provides a unified model linking aging-related metabolic stress, immune activation, and intercellular communication in AMD. Exosome-mediated ncRNA signaling, therefore, represents a critical interface between retinal structural cells and immune cells, coordinating the molecular pathways that drive disease progression114. Understanding this mechanistic network not only enhances our understanding of AMD pathophysiology but also highlights potential therapeutic targets. Strategies aimed at modifying exosomal cargo, regulating ncRNA expression, or reprogramming macrophage polarization may offer novel approaches to restoring retinal immune balance and preventing disease progression. Because direct AMD-specific evidence on exosomal ncRNA-mediated macrophage polarization remains limited, this review also includes selected studies from related ocular inflammatory, angiogenic, and neurodegenerative disease models. These include diabetic retinopathy, uveitis, glaucoma, retinal ganglion injury, and neuroinflammation, where exosome biology, ncRNA regulation, macrophage or microglial activation, oxidative stress, and vascular remodeling have been studied more extensively. However, findings from these models should not be interpreted as direct AMD evidence. They are included only to provide mechanistic context and to identify candidate pathways that require validation in AMD tissues, ocular fluids, patient-derived samples, and AMD-specific experimental models115.
In summary, the exosome–ncRNA–macrophage axis represents a central regulatory framework in AMD, integrating cellular stress responses, immune signaling, and angiogenic pathways. Continued investigation into this complex communication network will be essential for translating mechanistic insights into innovative diagnostic and therapeutic strategies for age-related retinal degeneration116,117.
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Age-related macular degeneration (AMD) is a progressive, multifactorial, and largely irreversible retinal disorder driven by complex interactions among cellular stress, chronic inflammation, impaired lipid metabolism, and immune dysregulation. This review highlights the critical contributions of retinal pigment epithelium (RPE) dysfunction, oxidative and mitochondrial damage, hemodynamic alterations, and complement activation in initiating and accelerating retinal degeneration during aging. Increasing evidence also ident...
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