Extracellular vesicles in erectile dysfunction: a narrative review of multicellular regulation

Introduction

Erectile dysfunction (ED) is a widespread male sexual health disorder defined as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance (1). It affects more than 150 million men worldwide, and its incidence is expected to increase with population aging and the growing prevalence of conditions such as diabetes mellitus (DM), cardiovascular disease, and metabolic syndrome (2). ED is particularly common in patients with DM and in individuals undergoing pelvic surgery associated with cavernous nerve injury (CNI), both of which are linked to more severe and treatment-resistant forms of ED (3). Beyond physical impairment, ED also affects psychological well-being, interpersonal relationships, and overall quality of life (1). These observations highlight the heterogeneity and clinical complexity of ED.

The pathophysiology of ED is complex and involves coordinated dysfunction of vascular, neural, smooth muscle, stromal, and immune components (4). Endothelial dysfunction, smooth muscle loss or phenotypic alteration, CNI, extracellular matrix (ECM) remodeling, and chronic inflammation disrupt the structural and functional integrity of the corpus cavernosum (5,6). Oxidative stress further damages the tissue (7). These interconnected processes form a complex regulatory network that makes it difficult to identify single-target therapeutic strategies and underscores the need for approaches that address multiple interconnected pathways.

Current treatments mainly offer symptomatic relief but fail to address underlying tissue alterations. Phosphodiesterase type 5 inhibitors improve erectile function by enhancing nitric oxide (NO)-mediated vasodilation (8), but their effectiveness is limited in patients with significant endothelial or neural impairment (9). In addition, these treatments do not reverse structural damage such as fibrosis or smooth muscle loss (10). These limitations highlight the need for therapeutic strategies that restore both structural integrity and functional coordination of erectile tissue.

The corpus cavernosum is composed of a specialized multicellular microenvironment consisting of endothelial cells, smooth muscle cells, fibroblasts, pericytes, immune cells, and neural elements (11). These cellular components are spatially and functionally interconnected, forming a coordinated neurovascular and stromal network that regulates penile hemodynamics and tissue homeostasis. Endothelial and smooth muscle structures are closely integrated with stromal, perivascular, and neural compartments within the corpus cavernosum (Figure 1). This organization supports dynamic interactions required for vascular regulation, structural stability, and erectile function. Disruption of these coordinated multicellular interactions contributes to the pathogenesis of ED, highlighting the multicellular network dysregulation seen in ED rather than dysfunction of a single cell type.

Figure 1 Multicellular organization of the CC and coordinated cellular interactions involved in erectile function. Schematic illustration of the penile CC showing the integrated multicellular microenvironment composed of endothelial cells, smooth muscle cells, fibroblasts, pericytes, immune cells, and neural elements. Cross-sectional anatomy of the penis demonstrates the spatial organization of the CC, TA, DV, urethra, and cavernosal vasculature. CA, cavernosal artery; CC, corpus cavernosum; DA, dorsal artery; DN, dorsal nerve; DV, dorsal vein; TA, tunica albuginea; UA, urethral artery; UV, urethral vein.

Extracellular vesicles (EVs) are recognized as mediators of intercellular communication within the corpus cavernosum (12,13). These membrane-bound particles, released by most cell types, carry bioactive cargo, including proteins, lipids, and nucleic acids, that can modulate recipient cell behavior (14). Thereby, EVs facilitate signaling across different cellular populations and facilitate coordinated tissue responses (15). EVs comprise a heterogeneous population of membrane-bound particles, including exosomes, microvesicles, and apoptotic bodies, which differ in their biogenesis and size distribution. Although the term exosome is frequently used in the literature, current recommendations favor the broader term EVs when vesicle origin cannot be definitively established. Common isolation and characterization approaches include ultracentrifugation, size-exclusion chromatography, nanoparticle tracking analysis, electron microscopy, and detection of EV-associated markers. EV-mediated communication drives interconnected processes in erectile tissue, including vascular regulation, neurovascular signaling, and stromal remodeling, which are interconnected processes in erectile tissue (Figure 2) (16). This way, EVs link multiple pathological pathways in ED. Compared with cell-based therapies, EV-based approaches may offer advantages such as lower immunogenicity, reduced tumorigenic risk, improved storage stability, and easier manufacturing and quality control. Although preclinical studies have generally demonstrated favorable safety profiles, issues related to biodistribution, off-target accumulation, and long-term toxicity remain important considerations for future clinical translation. However, the mechanisms underlying these coordinated effects remain incompletely defined.

Figure 2 EV-mediated multicellular regulation in ED. Schematic illustration of EV-mediated intercellular communication within the erectile tissue. EVs released from endothelial cells, smooth muscle cells, fibroblasts, pericytes, immune cells, and neural elements transfer bioactive cargo, including miRNAs, mRNAs, proteins, and lipids, to recipient cells within vascular, neural, and stromal compartments. EV-mediated signaling regulates interconnected biological systems involved in erectile tissue homeostasis, including vascular regulation, neurovascular signaling, and stromal remodeling. ECM, extracellular matrix; ED, erectile dysfunction; eNOS, endothelial nitric oxide synthase; EV, extracellular vesicle; miRNAs, microRNAs; mRNAs, messenger RNAs; NO, nitric oxide; PI3K/Akt, phosphoinositide 3-kinase/protein kinase B; TGF-β, transforming growth factor beta.

This review aims to summarize current evidence on EVs in ED, with an emphasis on their roles in multicellular communication within the corpus cavernosum. By integrating findings across different cellular sources, signaling pathways, and multicellular regulatory networks, the review highlights how EV-mediated signaling regulates multiple processes within erectile tissue and discusses their potential as precision therapeutic and diagnostic strategies for ED. We present this article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0471/rc).

Methods

A literature search was conducted using the PubMed database to identify studies related to EVs in ED. The search was conducted up to March 31, 2026 (Table 1). Search terms included “extracellular vesicles”, “exosomes”, “erectile dysfunction”, “angiogenesis”, “neuroregeneration”, “fibrosis”, “smooth muscle”, and “penile erection”. Studies were selected based on their relevance to EV biology and their contribution to understanding EV function in erectile tissue. Both experimental and translational studies were included, including in vitro studies, animal models of DM and CNI, and available human data. Only studies published in English were included.

Discussion

Mechanistic framework

Erectile function relies on coordinated interactions among vascular, neural, smooth muscle, stromal, and immune components within the corpus cavernosum (17). This multicellular organization underlies both normal erectile physiology and its dysregulation in ED. EVs function as important mediators of intercellular communication within this network as they facilitate the transfer of proteins, lipids, mRNAs, and microRNAs between different cell populations (12,18).

EV-mediated signaling regulates multiple interconnected biological systems involved in erectile tissue remodeling and dysfunction in ED, including vascular regulation, neurovascular signaling, and stromal remodeling (Figure 2) (19-24). EVs modulate cellular behavior across distinct tissue compartments by assisting the delivery of bioactive cargo and activation of coordinated signaling networks. Within vascular compartments, EVs promote endothelial proliferation, migration, NO signaling, and microvascular integrity, all of which support angiogenesis and penile hemodynamics (19,23,25-29). In neural and smooth muscle components, EV-mediated signaling contributes to axonal regeneration, neurotrophic support, nitrergic nerve function, smooth muscle survival, and maintenance of the contractile phenotype (21,22,30-37). In stromal compartments, EVs regulate ECM turnover, fibrosis modulation, oxidative stress responses, and tissue remodeling (24,32,38-40). These effects are closely associated with EV cargo composition. MicroRNAs, including miR-21-5p, miR-145, miR-148a-3p, and miR-30a-5p, are involved in angiogenesis, anti-apoptotic signaling, neurovascular regeneration, and fibrosis regulation through pathways involving phosphoinositide 3-kinase/protein kinase B, endothelial NO synthase/NO, transforming growth factor beta/Smad, phosphatase and tensin homolog, and Pyruvate Dehydrogenase Kinase 4-associated signaling (20,22,26,35,39,41,42). These pathological processes are functionally interconnected. Oxidative stress impairs endothelial NO signaling, promotes smooth muscle apoptosis, and enhances ECM deposition, linking vascular dysfunction, neural impairment, and fibrosis within a shared pathological framework (20,24,32,36,40). Taken together, these observations support a systems-level model in which EVs function as integrative regulators of multicellular neurovascular remodeling in ED. However, EVs have mostly been studied in the context of individual signaling pathways. Direct evidence demonstrating their coordinated multi-system regulation within a unified biological context remains limited and is mainly derived from preclinical studies rather than integrated in vivo analyses of multicellular regulation (43-47).

Evidence integration: convergent functional patterns of EVs in ED

EVs, particularly those derived from mesenchymal stem cells (MSCs), adipose-derived stem cells, urine-derived stem cells, pericytes, and Schwann cells, have demonstrated consistent therapeutic effects across experimental models of ED (20,21,23,31,33). These effects converge on several interconnected biological systems involved in erectile tissue homeostasis, including vascular regulation, neurovascular signaling, stromal remodeling, anti-apoptotic regulation, and oxidative stress responses (Table 2). In vascular compartments, EV enhances endothelial recovery, increases NO signaling, improves angiogenesis, and restores microvascular integrity (23,26,28,29). In neural and smooth muscle components, EV-mediated signaling promotes axonal regeneration, neurotrophic support, nitrergic nerve recovery, smooth muscle survival, and maintenance of contractile phenotype (22,30,34-36). Within stromal compartments, EVs attenuate fibrosis, regulate ECM turnover, and reduce oxidative stress-associated tissue remodeling (24,32,39,40). Importantly, these functional effects are observed across multiple ED contexts, including DM, CNI, aging-associated ED, and vascular injury models, suggesting that EV-mediated regulation is reproducible despite differences in disease etiology and experimental conditions (33,37,42,48). This broad impact likely reflects how complex EV cargo simultaneously targets multiple signaling pathways across different cells, rather than relying on a single mechanism.

Evidence summarized in Table 2 further suggests that EV-mediated therapeutic effects converge across multiple interconnected biological systems rather than acting through isolated pathways. Despite differences in EV sources and experimental models, preclinical studies consistently demonstrate coordinated improvements in endothelial recovery, neurovascular signaling, smooth muscle preservation, fibrosis modulation, and oxidative stress regulation. These findings support the concept that EVs function as integrative regulators of multicellular tissue remodeling in ED.

Despite these encouraging findings, several important limitations remain. Most studies are based on small animal models with relatively short follow-up periods. Moreover, outcome measurements are frequently restricted to functional assessments based on intracavernous pressure. These limitations preclude the definitive assessment of long-term structural recovery or translation into clinical settings. Direct comparisons between EV sources are also limited, making it difficult to determine their relative therapeutic efficacy. In addition, variations in EV cargo composition, dosing strategies, isolation methods, and experimental conditions contribute substantially to inter-study heterogeneity (43-45,47). Because most investigations continue to focus on isolated signaling pathways or outcome-specific measurements rather than integrated analyses across multiple biological systems, the in vivo coordination of EV signaling remains poorly understood. Together, these limitations highlight the need for standardized, mechanism-driven, and systems-level approaches to better define the therapeutic potential of EVs in ED.

Cellular origin determines functional specialization of EVs

The biological effects of EVs are strongly influenced by their cellular origin, resulting in distinct patterns of functional specialization within erectile tissue (20-24,34,49). Different EV populations preferentially regulate specific biological systems involved in erectile function rather than exerting identical effects across all tissue compartments (Table 3).

EVs that regulate endothelial activities primarily influence angiogenesis, NO signaling, endothelial recovery, and maintenance of microvascular integrity (23,25-28). EVs derived from smooth muscle cells are more closely associated with preservation of contractile phenotype, smooth muscle survival, and anti-apoptotic signaling (24,41). Pericyte-derived EVs promote vascular stabilization, neurovascular coupling, and microvascular support (22). Schwann cell-derived EVs preferentially promote axonal regeneration, neurotrophic signaling, and recovery of nitrergic nerve function following CNI (30,34). Fibroblast-associated EVs facilitate ECM turnover, stromal remodeling, and fibrosis regulation, with functional effects varying according to the activation state of the fibroblast (38,49). Despite these source-dependent differences, substantial functional overlap between EV populations should also be considered. Stem cell-derived EVs, particularly those derived from MSCs and adipose tissue-derived stem cells, drive broader regenerative effects involving angiogenesis, anti-apoptotic signaling, fibrosis modulation, oxidative stress regulation, and neurovascular restoration (19-21,23,29,33,39,40). This broader activity likely reflects the complexity of EV cargo composition, including microRNAs, growth factors, lipids, and regulatory proteins, capable of simultaneously modulating multiple signaling pathways across distinct cellular compartments. Consequently, stem cell-derived EVs are often associated with more consistent functional improvement across different ED contexts (43,45).

Collectively, these observations suggest that EVs exhibit relatively specialized or more integrative functional profiles depending on their cellular origin and cargo composition. This concept is consistent with the multicellular network framework illustrated in Figure 2. However, the optimal selection of EV sources for therapeutic application remains uncertain. Without direct comparisons, the relative efficacy of EV populations remains unclear. Moreover, EV function is influenced by cellular state, environmental context, and cargo composition. Fibroblast-associated EVs derived from activated stromal populations can promote fibrosis, whereas EVs from less activated populations may promote alternative remodeling (38,49). These findings suggest that the selection of EV sources should be guided by the dominant pathological features of ED within specific clinical contexts.

Current limitations and translational challenges

Despite encouraging preclinical findings, several important challenges continue to limit the clinical translation of EV-based therapies for ED. These limitations highlight a substantial gap between promising experimental outcomes and clinically applicable regeneration strategies. EV heterogeneity and lack of standardization are likely the most critical barriers to translation (43-47,50).

EV heterogeneity poses a major challenge because cellular origin, activation state, environmental conditions, and isolation methodology tightly dictate vesicle composition. Variability in cargo profiles, including microRNAs, proteins, lipids, and signaling molecules, directly affects biological activity and contributes to inconsistent functional outcomes across studies. This diversity may provide therapeutic flexibility, but it also complicates reproducibility, inter-study comparability, and the establishment of standardized therapeutic protocols.

Another important limitation is the heavy reliance on small animal models, particularly DM and CNI models. While these systems reproduce some pathological aspects of ED, they fail to fully recapitulate the complexity of human disease, including aging-associated tissue degeneration, systemic comorbidities, chronic inflammation, and long-term progression. In addition, most published studies have had relatively short follow-up periods and primarily relied on intracavernosal pressure-based functional measurements, which may not fully reflect long-term structural recovery or durable tissue remodeling (19,21,23,24,29,33,36,37,40).

Standardization of EV isolation, characterization, and dosing strategies also remains insufficient. Different isolation techniques, including ultracentrifugation, precipitation-based methods, and size-exclusion chromatography, generate EV populations with distinct physicochemical and biological properties. Variability in dosing regimens, administration routes, and purification protocols further contributes to inconsistency across studies and represents a major obstacle for regulatory approval and large-scale clinical implementation (43-47).

There are also mechanistic and delivery-related limitations. Most studies have focused on isolated signaling pathways or single functional outcomes rather than on investigating integrated multicellular regulation across vascular, neural, smooth muscle, and stromal compartments (Figure 2). Consequently, the systems-level mechanisms by which EV-mediated signals coordinate erectile tissue homeostasis remain poorly understood. In parallel, systemically administered EVs may accumulate in off-target tissues, reducing therapeutic efficiency and raising safety concerns. The limited targeting specificity of EVs further restricts their accumulation within the corpus cavernosum, which is critical for therapeutic efficacy (26,33,48). Biomaterial-assisted EV delivery systems, including hydrogel-based retention platforms and engineered targeting approaches, may help address some of these limitations by enhancing local retention, sustained release, and tissue specificity (25,33,48). However, scalable production systems, standardized manufacturing protocols, and long-term safety validation are necessary before the clinical transition of EV-based therapies. Addressing these challenges will be essential for advancing EV-based strategies from experimental models toward precision regenerative therapy.

Future perspectives: toward precision EV-based therapy

Future progress in EV-based therapy for ED will depend on overcoming current translational limitations while advancing toward more precise and mechanism-driven therapeutic strategies. Standardization of EV isolation, characterization, quantification, and quality control remains a priority, as variability in EV cargo composition and production methods affects reproducibility across studies (43-47,50). There is a need for unified criteria for EV classification and manufacturing to facilitate inter-study comparability, regulatory approval, and development of clinically applicable EV platforms.

Context-dependent functional specialization of EV populations is an important step. As summarized in Table 3, EVs derived from different cellular origins exhibit preferential associations with vascular regulation, neurovascular signaling, stromal remodeling, fibrosis modulation, or neuroregeneration (20,22,31,33,34,41,49). These observations suggest that EV-based therapies may ultimately require tailored approaches rather than uniform treatment strategies. For example, EV populations enriched for angiogenic signaling may be more suitable for diabetic ED characterized by endothelial dysfunction, whereas neuroregenerative EVs may be more appropriate for CNI-associated ED (20,22,23,31,33,34). This concept aligns with the multicellular network framework illustrated in Figure 2 and supports the development of precision regenerative approaches targeting dominant pathological components within specific ED contexts.

Further advances will also depend on improved mechanistic understanding and continued development of EV engineering technologies. Integrating single-cell RNA sequencing, proteomics, metabolomics, and spatial transcriptomics may help define EV-mediated communication networks and clarify how cargo composition shapes multicellular tissue responses. Programmable EV engineering strategies, including cargo modification, microRNA enrichment, surface functionalization, and tissue-targeting approaches, may improve therapeutic specificity and reduce off-target distribution (26,35,42,51). Biomaterial-assisted delivery systems, such as hydrogel-based local retention platforms and sustained release scaffolds, may further enhance intracavernosal accumulation and prolong therapeutic activity (25,33,48).

Artificial and synthetic EV platforms are emerging as promising approaches to overcome several limitations of naturally secreted EVs, including low yield, cargo heterogeneity, and limited targeting specificity (52-54). These systems include artificial vesicles, biohybrid EVs, and cell-derived nanovesicles generated through membrane engineering or mechanical extrusion technologies (55-58). Artificial vesicles can be loaded with defined therapeutic cargo, whereas biohybrid systems combine natural EV membranes with synthetic nanomaterials to improve stability, biodistribution, and tissue targeting (59-62). Cell-derived nanovesicles may provide scalable EV-like platforms while retaining important biological properties of parental cells (52,63,64). Although these technologies have not yet been extensively investigated in ED, studies in cardiovascular, neurological, and regenerative medicine have demonstrated their ability to regulate angiogenesis, inflammation, oxidative stress, fibrosis, and tissue repair (52,54,65). Future studies should determine whether engineered EV platforms can be adapted to target endothelial dysfunction, neurovascular injury, fibrosis, and smooth muscle loss in ED.

Translational progress will additionally require scalable production systems compatible with Good Manufacturing Practice standards, together with rigorous safety evaluation and long-term efficacy assessment. Early-phase clinical studies focusing on dosing, biodistribution, administration routes, and long-term tissue remodeling will be essential for determining feasibility in human ED. EVs also have potential as biomarkers for disease stratification, treatment monitoring, and prediction of therapeutic responsiveness, which can be studied through circulating or tissue-specific EV cargo profiles (43-45,47).

Combination strategies integrating EVs with current pharmacological, neuromodulatory, or biomaterial-based therapies may allow simultaneous targeting of multiple pathological systems involved in ED. Continued advances in bioengineering, nanotechnology, and systems biology are likely to further expand the therapeutic potential of EVs and support the development of precision regenerative therapies capable of coordinately restoring vascular, neural, smooth muscle, and stromal function within the corpus cavernosum. Together, these developments may help bridge the gap between experimental findings and clinically applicable EV-based therapy for ED.

Conclusions

EVs are important mediators of multicellular communication within the erectile tissue. EVs can transfer bioactive cargo to regulate interconnected processes involving vascular regulation, neurovascular signaling, smooth muscle maintenance, stromal remodeling, fibrosis, and oxidative stress. A systems-level view portrays ED as a disorder of multicellular neurovascular dysregulation rather than dysfunction of a single pathway. EV-based approaches may provide therapeutic benefits across multiple ED contexts, including DM and CNI. In addition, EV function appears to depend on cellular origin and cargo composition, supporting the concept of functional specialization and context-dependent therapeutic application. Despite these promising findings, critical challenges remain: EV heterogeneity, lack of standardization, unclear mechanisms, and minimal clinical validation. Advances in EV engineering, delivery systems, and translational research will help establish precision EV-based therapies tailored to specific pathological subtypes of ED.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0471/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0471/prf

Funding: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. RS-2025-00513774, to J.K.R.) and the Inha University Research Grant (to J.K.R.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0471/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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