Abstract
Introduction
Erectile dysfunction and Peyronie’s disease are prevalent and frequently coexisting disorders in which guideline-based therapies improve symptoms more reliably than they reverse underlying corporal remodeling or tunical fibrosis. Regenerative biologics and nano-enabled delivery systems aim to intervene upstream in inflammatory and fibrotic pathways by improving local exposure, tissue persistence, and target engagement within the emerging field of regenerative sexual medicine.
Objectives
To synthesize current evidence on regenerative biologics and nano-enabled delivery platforms for erectile dysfunction and Peyronie’s disease, with emphasis on disease-specific delivery barriers, payload characterization, and translational readiness.
Methods
This article was designed as a narrative translational review informed by a scoping search of PubMed/MEDLINE, Embase, and Web of Science (January 2000 to March 2025), supplemented by hand-searching of reference lists. Evidence was synthesized qualitatively by disease context (erectile dysfunction vs Peyronie’s disease), payload class, delivery constraints, and translational maturity.
Results
For erectile dysfunction, platelet-rich plasma has widespread clinical uptake but remains limited by heterogeneous preparation methods, placebo susceptibility, and rapid corporal washout. Early stem cell studies support feasibility, yet converging mechanistic evidence suggests that paracrine signaling predominates, favoring acellular approaches such as extracellular vesicles (EVs) delivered with hydrogels or engineered nanocarriers. For Peyronie’s disease, intralesional collagenase clostridium histolyticum (CCH) remains the current clinical benchmark for plaque-targeted minimally invasive therapy in selected stable disease, whereas platelet-rich plasma and cell/vesicle-based approaches remain investigational. Across Peyronie’s disease platforms, dense plaque architecture, restricted diffusion, and calcification constrain intralesional exposure, supporting plaque-confined depots, matrix-interactive materials, and targeted antifibrotic nanomedicines.
Conclusion
Regenerative sexual medicine is evolving from empiric biologic injections toward better-characterized, anatomy-aligned, exposure-controlled therapeutic platforms, where durable clinical benefit will depend on sustained target engagement within penile tissues. Near-term progress is most likely through phenotype-enriched early-phase trials with rigorous sham-aware design and objective hemodynamic or imaging endpoints, whereas longer-term translation will depend on standardized potency assays, reproducible manufacturing, and durable penile tissue targeting.
Keywords: erectile dysfunction, Peyronie’s disease, nanomedicine, extracellular vesicles, exosomes, platelet-rich plasma, mesenchymal stromal cells, hydrogels, fibrosis, drug delivery systems, tissue engineering, regenerative medicine
Introduction
Erectile dysfunction (ED) and Peyronie’s disease (PD) frequently coexist and impose a substantial psychosocial burden through impaired sexual function, reduced quality of life, and relationship distress. Currently recommended guideline-based therapies may improve erections and penile deformity, yet they rarely reverse underlying penile hemodynamic impairment or corporal/tunical fibrosis. As a result, many patients achieve symptomatic control without clinically meaningful tissue recovery, leaving a persistent unmet need for disease-modifying strategies.1–3 Therapies that fail to alter the underlying disease trajectory are therefore vulnerable to waning long-term efficacy, particularly in ED.
ED is increasingly recognized as a manifestation of progressive vascular and neural injury within the corpora cavernosa rather than a purely functional disturbance of penile rigidity. This conceptual shift aligns ED with chronic disease biology and helps explain why long-term recovery is uncommon once structural remodeling and compliance loss are established.4 In parallel, PD exemplifies aberrant, localized wound healing within the tunica albuginea, characterized by plaque formation and biomechanical distortion that may persist even after pain resolves and curvature stabilizes.5,6 Within a personalized medicine framework, these conditions are best conceptualized as heterogeneous remodeling phenotypes defined by dominant injury biology, anatomic compartment, and disease stage. Such framing informs regenerative payload selection, delivery route, and endpoint choice.
Across ED and PD, oxidative stress, chronic inflammation, and dysregulated extracellular matrix (ECM) remodeling act as convergent biological hubs that promote tissue stiffening and microvascular dysfunction.7,8 In ED, combined vascular and neural injury promotes endothelial dysfunction, smooth muscle loss, and ECM deposition, reducing corporal compliance and compromising veno-occlusion; cavernous nerve injury (CNI) after pelvic surgery and diabetes-associated microvascular disease accelerate this trajectory through oxidative and inflammatory signaling.9,10 In contrast, PD reflects aberrant wound healing within the tunica albuginea, leading to a localized fibrotic plaque sustained by persistent fibroblast activation, myofibroblast differentiation, and profibrotic signaling networks.11,12 Single-cell transcriptomic profiling supports a sustained immunofibrotic plaque microenvironment with durable immune-cell infiltration and signaling beyond early inflammatory disease.13 Variable natural history underscores the limitations of uncontrolled series and reinforces the need for phase- and phenotype-stratified clinical trials.14
These anatomic and biological distinctions impose delivery constraints that substantially influence therapeutic efficacy. In ED, key disease nodes—including CNI, hypoxia-driven smooth muscle loss, and endothelial dysfunction—reside within a highly perfused corporal compartment, where rapid dispersion and venous drainage promote washout and can limit target engagement after bolus intracavernosal delivery.15–18 In PD, the dominant substrate is a spatially confined collagen-dense immunofibrotic plaque within the tunica albuginea, where penetration, diffusion, and retention represent the principal barriers to effective exposure.19–21 Accordingly, platforms must align mechanism with anatomy by prioritizing neurovascular target engagement in high-flow compartments for ED and sustained, plaque-confined delivery for PD.22,23 Key regenerative biologics and nano-enabled delivery platforms for ED and PD are summarized in Table 1, while the principal barriers to plaque-confined exposure in PD are highlighted in Table 2.
Table 1.
Regenerative biologics and nano-enabled delivery platforms investigated for erectile dysfunction (ED) and Peyronie’s disease (PD), summarized by disease target, delivery strategy, intended biological effect, and current level of evidence. Emphasis is placed on the interaction between biological payload and delivery kinetics, underscoring why inadequate exposure control, tissue barriers, and mechanistic mismatch may limit durable clinical efficacy despite biological potency.
| Platform/payload | Target (ED vs PD) | Delivery approach | Intended biological effect | Evidence stage & key limitations |
|---|---|---|---|---|
| Platelet-rich plasma (PRP) Platelet-rich fibrin (PRF/PRFM) |
|
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| Mesenchymal stromal cells (MSCs) (eg, adipose, bone marrow, Wharton’s jelly) |
|
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| Extracellular vesicles (EVs)/exosomes (cell- or PRP-derived; engineered EVs) |
|
|
|
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| Nano-enabled small molecules (redox/NO modulation platforms) |
|
|
|
|
| Injectable depots and hydrogels (thermosensitive/stimuli-responsive; plasma-derived gels) |
|
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|
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| Targeted antifibrotic nanomedicine (eg, ALK5 inhibitors; Gal-3/CTGF targeting; collagen-binding carriers) |
|
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|
|
Abbreviations: ED, erectile dysfunction; PD, Peyronie’s disease; PRP, platelet-rich plasma; PRF/PRFM, platelet-rich fibrin/matrix; MSCs, mesenchymal stromal cells; EVs, extracellular vesicles; NO, nitric oxide; ALK5, transforming growth factor-beta type I receptor (activin receptor-like kinase 5); Gal-3, galectin-3; CTGF, connective tissue growth factor.
Table 2.
Central barriers to plaque-confined therapy in Peyronie’s disease and their implications for disease-modifying delivery.
| Barrier | Why it matters in PD | Design implication |
|---|---|---|
| Dense collagen-rich plaque matrix | Restricts interstitial diffusion and creates heterogeneous intraplaque exposure after bolus injection. | Favor plaque-confined depots, matrix-interactive carriers, or release systems that prolong local residence. |
| Calcification and plaque heterogeneity | Can hinder needle placement, reduce uniform distribution, and limit access to biologically active niches. | Stratify by calcification status and document plaque phenotype with imaging before and during trials. |
| Small focal target within a mechanically critical tunica | Off-target spread may miss the plaque and expose normal tunica to unnecessary drug or biomaterial. | Use image-guided placement and formulations engineered for uniform distribution within the lesion. |
| Short-lived exposure of soluble mediators | Brief contact may be insufficient to alter myofibroblast activity or extracellular matrix turnover. | Use sustained-release hydrogels, scaffolds, or repeated low-volume delivery plans guided by residence data |
| Need to preserve tunical biomechanics | Persistent or overly stiff materials may add nodularity, stiffness, or deformity. | Match degradation and mechanical profile to tunical tissue and monitor pain, nodularity, and curvature. |
Current clinical management differs meaningfully between ED and PD. In ED, guideline-based care leverages residual neurovascular responsiveness without rebuilding cavernosal structure.24,25 In PD, mechanical, intralesional, and surgical approaches may reduce deformity, and intralesional collagenase clostridium histolyticum (CCH) remains the most clinically validated plaque-targeted minimally invasive therapy for selected stable disease; however, even CCH does not reliably normalize the underlying fibrotic plaque biology across phenotypes.26–28 These limitations have catalyzed regenerative sexual medicine, which seeks durable recovery through restoration of cavernosal neurovascular architecture in ED and interruption or partial reversal of plaque remodeling in PD. The field is now shifting toward smart delivery systems and nanomedicine platforms that prioritize tissue repair rather than symptom management.26–28
This narrative translational review examines ED and PD in parallel while maintaining disease-specific emphasis. It appraises the comparative rationale for regenerative biologics and nano-enabled delivery platforms in each condition, delineates how disease-specific barriers, such as corporal washout in ED and diffusion limitations within tunical plaques in PD, constrain target engagement, and identifies trial-design features necessary to distinguish true disease modification from placebo effects and the expected natural history.
Methods
Review design and search strategy
This article was designed as a narrative translational review informed by a scoping literature search rather than a formal systematic review or meta-analysis. Searches were performed in PubMed/MEDLINE, Embase, and Web of Science Core Collection for publications from January 2000 through March 2025. Search terms combined disease descriptors (ED, PD, penile fibrosis) with intervention and delivery-related terms (regenerative therapy, platelet-rich plasma, stem cells, mesenchymal stromal cells, extracellular vesicles (EVs), exosomes, nanomedicine, hydrogels, nanoparticles, and drug delivery). Reference lists of relevant reviews and primary studies were also hand-searched to identify additional articles. Priority was given to studies providing mechanistic insight, translational relevance, or clinical outcome data related to regenerative biologics and nano-enabled delivery platforms. Only articles published in English were considered. The full PubMed search strategy is provided in Appendix A.
Eligibility criteria
Included studies comprised preclinical in vivo and in vitro studies, early-phase clinical studies, observational cohorts, and randomized trials evaluating regenerative biologics or nano-enabled delivery strategies in ED or PD. Studies addressing biologic payload characterization, mechanisms of action, delivery performance, tissue remodeling, or safety outcomes were eligible.
Exclusion criteria included reports lacking mechanistic relevance, purely symptomatic pharmacologic studies without regenerative intent, and studies lacking relevance to penile tissue biology or delivery considerations.
Study selection and data extraction
Study selection was iterative and interpretive, consistent with a narrative/scoping review. Titles and abstracts were screened for topical relevance to regenerative mechanisms and delivery concepts in ED and PD, followed by full-text review for mechanistic and translational relevance. Data abstraction was qualitative and focused on study design, biologic or nanotechnology platform, route of administration, target compartment, mechanistic rationale, outcomes related to tissue remodeling or function, durability of effect, and reported safety signals. To avoid overstating methodological rigor, no duplicate screening, protocol registration, formal risk-of-bias assessment, or quantitative pooling was performed.
Synthesis approach
Evidence was synthesized narratively and organized by disease context (ED versus PD), biologic payload type, and delivery strategy. Emphasis was placed on aligning mechanism of action with anatomic compartment, delivery constraints, and translational readiness. Areas of consistency and uncertainty were highlighted, and findings were interpreted in the context of known limitations related to biologic heterogeneity, placebo susceptibility, and early-phase study design. Because a record-level PRISMA-style flow was not prospectively captured, Appendix A provides the exact PubMed search string and a staged narrative selection framework rather than a formal PRISMA diagram.
Ethics and reporting considerations
Institutional Review Board approval and informed consent were not required because this manuscript synthesized published literature only and did not involve human participants, animals, or identifiable personal data collected by the authors. No systematic-review management software, screening automation, or statistical synthesis software was used. The revised manuscript was prepared to improve transparency for a narrative review, but PRISMA or PRISMA-ScR procedures were not applied because formal systematic mapping and duplicate record accounting were not prespecified.
Nanotechnology enters sexual medicine
Nanomedicine has entered sexual medicine because delivery constraints represent a major barrier to disease modification in penile tissues.29 It encompasses nanoscale carriers and nano-enabled delivery systems engineered to control tissue localization, payload stability, cellular uptake, and release kinetics,30 including nanoparticles and nanovesicles, surface-functionalized formulations, and depot materials such as nanocomposite or stimuli-responsive hydrogels designed to sustain local exposure.31,32 Nano-enabled strategies are also relevant when the administered construct is not strictly nanoscale in size, as nanoscale engineering determines biodistribution, cellular uptake, or release behavior.33,34 Sustained target engagement within the appropriate penile compartment is often more consequential for biological effect than nominal particle size.34
Penile pharmacokinetics highlight the limitations of conventional delivery.18 Systemic administration commonly yields insufficient corporal exposure and increases off-target effects.35 Local injection achieves high concentrations, but is limited by rapid dispersion and venous outflow, reducing residence time and consistent target engagement.18 Nano-enabled carriers can overcome these constraints by stabilizing labile payloads, enhancing local bioavailability, and tuning release profiles to the timescale of tissue remodeling.34,35 Accordingly, nanotechnology is likely to achieve its greatest translational impact when paired with regenerative payloads in ED and PD, where spatiotemporal exposure control is a key determinant of durable biological effect.36,37
Nano-enabled pharmacologic and redox modulation strategies
Early formulation studies in ED models leveraged nanocarriers to deliver small molecules and redox-active compounds aimed at mitigating pathological tissue remodeling. Proof-of-concept experiments confirmed that nanoparticles loaded with erectogenic agents can localize to penile tissue and trigger erectile responses, establishing the feasibility of nanoscale topical drug delivery in ED.38 Notably, such nanoparticle-based delivery could bypass first-pass metabolism and avoid the hazards of intracavernosal injections, potentially improving the safety profile of therapy.38 In a type-2 diabetic rat model, topically applied curcumin-loaded nanoparticles improved erectile hemodynamics and modulated molecular markers of oxidative stress and inflammation.39 Likewise, in a diabetic rat model, locally administered nitric oxide (NO)–releasing polymeric microspheres improved erectile responses and potentiated the effect of sildenafil, supporting the concept that engineered local NO delivery can enhance downstream cGMP signaling in settings where endogenous NO bioavailability is compromised.40
However, not all nanomedicine formulations intrinsically reverse disease processes. For example, a nano-transfersomal transdermal film of sildenafil primarily optimizes drug absorption and systemic exposure for symptomatic relief, relying on improved pharmacokinetics rather than direct reversal of fibrotic or vascular pathology.41 Overall, these examples demonstrate that nano-enabled delivery systems can increase local drug exposure and influence upstream injury pathways. Nonetheless, enhanced delivery alone does not equate to true tissue regeneration unless paired with therapeutic payloads capable of actively reprogramming the remodeling process.
Injectable depots and controlled release
Injectable depot platforms, such as hydrogels and nanocomposite matrices, are designed to prolong local exposure and stabilize spatial distribution after local penile administration.42 Their translational appeal differs by disease. In PD, collagen-dense, diffusion-limited plaques make brief exposure unlikely to durably alter myofibroblast activity or ECM turnover.43 In ED, by contrast, the dominant obstacle is rapid corporal washout rather than tissue penetration. Beyond preclinical models, depot-based systems are attractive because they can address these pharmacokinetic limitations and sustain localized bioactivity at the site of disease.
For example, hydrogels used as scaffolds for photothermally biomodulated (PTBM) platelet-rich plasma (PRP) preparations enriched with exosomes may represent an effective delivery platform for targeting bioactive cargo to the corpora cavernosa or Peyronie’s plaques.44 Under these conditions, such systems could support neurovascular repair and regulate fibrotic remodeling through several complementary mechanisms.
First, hydrogels can retain and spatially concentrate regenerative signals by entrapping both exosomes and platelets within the PRP preparation. Entrapped platelets would continue to release the contents of their granules, including multiple growth factors, cytokines, and other bioactive molecules, while simultaneously providing sustained availability of platelet-derived exosomes. Second, the hydrogel scaffold could function as a protective microenvironment, shielding proteins and exosomes from rapid enzymatic degradation in vivo and thereby prolonging their biological activity. Third, gradual release of these bioactive components from the hydrogel matrix could enable sustained, long-term delivery of regenerative signals to the target tissue.45
Depot systems can further be engineered to respond to temperature, reactive oxygen species, or enzymatic signals, enabling adaptive release profiles within inflamed or fibrotic microenvironments.46
In ED, depot platforms address a different constraint because the corpora cavernosa are highly perfused and rapid washout can narrow the effective exposure window after bolus injection.47 By extending residence time, controlled release systems may sustain regenerative cues during the critical post-injury remodeling interval.48,49 These formulation advances suggest that residence time and spatial confinement often determine whether a locally delivered therapy achieves meaningful target engagement within penile tissues.42
Regenerative cue delivery and endogenous repair recruitment
Regenerative nano-platforms extend beyond pharmacologic exposure optimization alone by delivering “instructive” cues that may recruit endogenous repair mechanisms or reprogram remodeling. Such systems may deliver chemokines, morphogens, or regulatory nucleic acids to influence angiogenesis, neuroprotection, inflammation resolution, and antifibrotic signaling. A representative preclinical example is a black phosphorus-based platform used to deliver stromal cell-derived factor 1-alpha after CNI, illustrating the potential integration of recruitment cues with neurovascular repair pathways in neurogenic ED.50 This example should be interpreted as proof-of-concept rather than evidence of clinical efficacy.
Clinical translation: phenotype fit and systemic modifiers
Nanotechnology reframes penile therapeutics around tissue exposure, targeting, and persistence, with clinical performance increasingly determined by effective delivery to the intended tissue and sustained residence at relevant biological targets.51 The same payload may produce divergent biological effects depending on residence time, spatial distribution, and cellular uptake, all of which are influenced by particle design and local tissue barriers.52 This delivery-focused framework helps explain the inconsistent clinical signals observed with early regenerative injections and supports a shift toward engineered platforms that impose tighter control over localization and release.53 At present, most evidence supporting nano-enabled penile delivery derives from formulation studies and preclinical models, while human efficacy data remain limited.
In the near term, nano-enabled delivery may be most readily translated for ED, particularly post-prostatectomy neurogenic ED and diabetes-associated vasculometabolic ED, where rapid corporal washout and incomplete target engagement may be mitigated through exposure-controlled local depots or mucosal delivery strategies.54 For PD, translation is more likely to center on plaque-confined adjunct or comparator strategies in selected phenotypes rather than on replacement of currently used intralesional standards such as CCH.28 Systemic modifiers may further influence responses to locally delivered regenerative payloads; for example, gut microbiota dysbiosis has been linked to ED and may further reinforce oxidative stress and inflammatory signaling, supporting evaluation of microbiome-associated biomarkers for patient stratification or as covariates in early-phase studies.55–57 Accordingly, these near-term translation pathways should be interpreted as hypothesis-generating rather than as established clinical evidence.
These advances in delivery provide an enabling foundation. The first regenerative wave in sexual medicine relied largely on empiric biologic approaches with variable composition and limited control over tissue exposure.53 As shown in Figure 1, the field is shifting from short-lived, bolus biologic interventions to delivery platforms that enhance retention and enable more precise control of local bioactive exposure. The next section reviews these modalities, summarizes the available clinical evidence, and explains how current limitations have driven the development of nano-enabled delivery strategies.
Figure 1.
Second-generation biologics in sexual medicine and the shift toward exposure-controlled platforms. Schematic progression from empiric biologics (platelet-rich plasma, cells) to acellular extracellular vesicles (exosomes) and engineered delivery strategies (nanocarriers, injectable hydrogels/depots, and scaffolds) enabling increasing control of local tissue exposure. The timeline indicates approximate exposure duration from bolus/transient delivery to minutes, hours, and days. Abbreviations: PRP, platelet-rich plasma.
Biologics–platelet-rich plasma as the first regenerative wave in sexual medicine
Rationale and current evidence base
Among empiric biologic interventions proposed for penile regeneration, PRP is the most frequently discussed and widely used in clinical practice for ED and PD. Its biological rationale is supported by the ability of platelet-derived mediators can influence endothelial repair, microvascular remodeling, inflammatory signaling, and ECM turnover—processes central to corporal remodeling in ED and plaque biology in PD. However, its current clinical position differs by disease: in ED it remains investigational within a field lacking established regenerative therapy, whereas in PD it should be interpreted in relation to the existing intralesional benchmark of CCH for selected stable disease.28 Contemporary systematic reviews consistently report that, while PRP appears feasible and well tolerated, the certainty of clinical efficacy remains uncertain; although meta-analyses suggest an overall positive signal in ED, most reports emphasize substantial heterogeneity in product preparation, dosing definitions, and injection protocols across studies.58,59 These limitations have stimulated increasing interest in more standardized acellular biologics, particularly EVs and engineered delivery platforms, which aim to provide more reproducible regenerative signaling and improved tissue targeting.
Efficacy signals: controlled trials and placebo susceptibility
Erectile dysfunction
PRP therapy has been investigated as a potential regenerative treatment for ED, but current evidence remains mixed and inconclusive. Early randomized controlled trials reported that intracavernosal PRP injections modestly improved erectile function compared with placebo controls in men with mild to moderate ED.60–63 In the trial by Masterson et al., the absence of a between-group effect may partly reflect clinical and methodological heterogeneity, including enrollment across a broader ED severity spectrum with a relatively larger proportion of men with moderate disease, together with protocol features that differed from prior studies, such as PRP volume delivered and injection schedule.62,63 Notably, some trials did not enforce washout of phosphodiesterase-5 inhibitor medications, complicating interpretation of PRP’s independent effect.64 Moreover, no consensus standard exists for PRP preparation or dosing in ED. Across published studies, protocols differ substantially in PRP processing and administration, including wide variation in total injected volume (approximately 0.5-9 mL) and in the number and spacing of treatment sessions (commonly two to six injections), which limits cross-study comparability and complicates dose–response interpretation.58 Another concern is limited tissue exposure time after injection; PRP may diffuse or be rapidly carried away from erectile tissues. To mitigate rapid washout, some investigators have used temporary penile tourniquets or converted PRP into a platelet-rich fibrin matrix to improve local retention of growth factors at the target site.65 These methodological differences, together with the well-recognized placebo susceptibility of ED, highlight the challenge of defining PRP’s true efficacy.58
Overall, while most studies suggest that PRP injections may improve erectile function in selected patients, no consensus yet exists regarding its therapeutic value. PRP is not currently endorsed by major guidelines for ED, and further high-quality, placebo-controlled trials with standardized protocols are needed to define whether it has a reproducible role beyond investigational use.58
Peyronie’s disease
In contemporary PD practice, CCH remains the principal clinically validated intralesional therapy for selected stable disease, whereas PRP should still be regarded as an investigational biologic injection.28 However, access to CCH remains limited in several regions worldwide, highlighting the need for alternative plaque-targeted biologic strategies. Against this benchmark, early randomized evidence suggests that intralesional PRP is feasible and appears well tolerated in a phase 2 randomized, placebo-controlled crossover design.66 However, interpretation of efficacy is constrained by small sample size, heterogeneity in disease phase and, and the absence of standardized plaque imaging and prespecified patient-centered functional outcomes. Given the variable natural history of PD, uncontrolled case series and studies incorporating concomitant traction therapy, injections, or other co-interventions complicate attribution of treatment benefit. These limitations underscore the need for rigorous trial design with phase-specific enrollment, substrate-aware stratification, and well-defined outcome measures.67
Multimodal approaches that combine intralesional PRP with tunneling techniques and traction therapy have been proposed and are increasingly used in some practices. Within such protocols, the therapeutic limitation of PRP may lie less in biological inactivity than in insufficient intraplaque persistence after bolus injection, suggesting that strategies capable of prolonging intraplaque retention could strengthen combination approaches in PD.
Why PRP results vary: heterogeneity, exposure limits, and implications for next-generation platforms
Inconsistent efficacy signals reported for PRP in ED and PD are most plausibly explained by substantial product heterogeneity combined with limited control of tissue exposure.68,69 PRP composition varies markedly across preparation protocols and processing methods, with differences in platelet concentration, leukocyte content, activation strategy, and storage conditions, all of which can alter growth-factor profiles and inflammatory mediator release.70 This variability complicates meaningful comparisons across studies, precludes reliable dose–response inference, and hinders establishment of reproducible potency thresholds for clinical translation.71
Control of tissue exposure remains an additional important constraint, as standard injection techniques provide limited spatiotemporal regulation following administration. In ED, intracavernosal injection is performed within a highly perfused compartment, where venous drainage may shorten tissue residence time and promote rapid systemic redistribution of soluble mediators.72 In PD, intralesional delivery is further challenged by dense fibrotic tissue characterized by excessive collagen accumulation and persistent myofibroblast activity, which can impede uniform penetration and result in heterogeneous intraplaque distribution following bolus injection.73 Consequently, larger injected volumes do not necessarily translate into enhanced biological efficacy when active mediators are rapidly dispersed, degraded, or fail to reach the most relevant cellular targets within corporal tissue or plaque microdomains.74
Taken together, PRP has catalyzed interest in disease-modifying approaches in sexual medicine while simultaneously highlighting the need for standardized potency assessment and exposure-controlled delivery. These limitations support next-generation strategies that integrate PRP bioactivity with engineered delivery systems that stabilize local retention and prolong tissue residence, enabling dosing based on quantifiable product attributes rather than preparation-dependent volume alone.75 Such strategies may rely on scaffold-based and sustained-release platforms to anchor bioactive mediators within the target microenvironment.
In the near term, investigational application currently appears most plausible in mild to moderate vasculogenic ED and in selected PD phenotypes—particularly early or stable noncalcified plaques—where local retention and sustained intralesional exposure may be biologically actionable. Even in these settings, however, such strategies should currently be viewed as investigational complements or comparators rather than replacements for established CCH-based management in appropriate selected stable PD phenotypes.28
Stem cells and extracellular vesicles as natural nanoparticles
MSC therapy: preclinical signals and early clinical feasibility
Across rodent models of diabetic ED, CN), pelvic irradiation, and aging, intracavernosal delivery of mesenchymal stromal cells (MSCs) has been associated with improvements in erectile hemodynamics and favorable remodeling biomarkers. Reported tissue-level effects are broadly consistent with enhanced endothelial signaling, preservation of smooth muscle content, and reduced collagen deposition.76 A meta-analysis focused on diabetic ED similarly reported convergent functional improvement across stem cell studies, supporting a reproducible reparative phenotype despite heterogeneity in experimental models and cellular sources.77
Early-phase human studies suggest that intracavernosal cell-based interventions can be delivered without major short-term safety signals, although durable restorative efficacy remains unproven. Intracavernosal injection of autologous adipose-derived regenerative cells after radical prostatectomy was feasible, with functional improvement reported in subsets of participants.78 A phase 1/2 pilot study evaluating intracavernosal bone marrow mononuclear cells for post-prostatectomy ED also supported feasibility, without major safety concerns, while highlighting the limitations of small, uncontrolled designs for demonstrating durable restoration.79 In diabetes-associated ED, repeated intracavernosal Wharton’s jelly MSC administration provided additional feasibility and safety signals and illustrated the potential importance of dosing frequency when therapeutic effects are mediated by transient paracrine exposure rather than durable engraftment.80 Consistent with these findings, a 2025 systematic review and meta-analysis of human stem cell trials reported significant improvements in erectile function scores and penile hemodynamic parameters at six months post-treatment compared to baseline, although long-term efficacy remains insufficiently demonstrated.81
MSCs are a class of multipotent cells capable of differentiating into multiple cell types. However, their therapeutic potential extends well beyond direct cellular differentiation.82 Increasing evidence indicates that MSCs exert their regenerative effects primarily through modulation of the local tissue environment via paracrine signaling. Notably, several preclinical studies demonstrate that long-term engraftment of transplanted MSCs within penile tissue is minimal, further supporting the concept that their therapeutic effects are largely mediated by transient paracrine signaling rather than durable cellular integration. In this context, MSCs secrete a broad range of biologically active molecules, including cytokines, chemokines, growth factors, and EVs, which collectively influence surrounding cells within damaged tissues.83
From cells to extracellular vesicles: the paracrine rationale
Most therapeutic effects observed following MSC administration appear to be mediated by secreted paracrine factors rather than durable cellular engraftment. This has prompted a shift from cell-based approaches toward their secretome, with particular emphasis on EVs. More recently, attention has also expanded to the broader cell-derived secretome, which includes extracellular vesicles together with soluble proteins, cytokines, and growth factors that collectively shape the regenerative microenvironment. MSC-derived EVs can be leveraged as acellular, biologically active “natural nanoparticle” therapies, offering advantages such as improved standardization, reduced safety concerns, and controlled delivery. EVs comprise a heterogeneous population of membrane-binding particles, including exosomes, microvesicles, and apoptotic bodies. Exosomes, due to their endosomal origin, nanoscale size, biological stability and enriched signaling cargo, are positioned as principal biological effectors with superior tissue penetration and therapeutic potential compared with other EV subtypes. Therefore, product specificity and mechanistic attribution require cautious interpretation and biological characterization.84,85
EVs function as endogenous nanoparticles that transport diverse cargos, including microRNAs, proteins, lipids, and growth factors, capable of modulating gene expression programs in recipient cells. Through coordinated paracrine signaling, EVs influence endothelial repair, neuroprotection, inflammation modulation, and antifibrotic pathways, processes that are directly relevant to tissue remodeling in ED and PD.86,87
For clinical translation, EV potency is cargo- and context-dependent and should be defined through indication-aligned functional assays rather than particle number alone.88 Position papers on EV-based medicinal products emphasize that release criteria should document identity and purity through orthogonal approaches, including size distribution and particle quantification, vesicle-associated marker profiles, and practical metrics such as a particle-to-protein ratio as a surrogate for non-vesicular carryover.89 Recent good manufacturing practice (GMP) reports further demonstrate how sterility and endotoxin testing, alongside with prespecified potency assays, can be incorporated into lot-release strategies for EV-enriched products intended for early-phase clinical trials.90 In preclinical synthesis, a systematic review and meta-analysis of stem cell-derived EV therapy in animal models reported a large overall effect on erectile function, with a standardized mean difference of 3.68 for the intracavernosal pressure to mean arterial pressure ratio.91 While this convergence supports the concept that EVs can deliver meaningful, multi-pathway repair signals, it also highlights that delivery and exposure are likely to be critical determinants of clinical translation.
Importantly, exosomes can be efficiently generated from PRP, as platelets represent a rich and accessible source of EVs. Controlled platelet activation promotes exosome release with biologically active cargo relevant to tissue repair and remodeling.92 In addition, several PRP preprocessing strategies have been shown to enhance exosome release. Among these, emerging evidence suggests that PTBM of PRP may represent a promising approach to induce and modulate exosome release.
PRP-derived exosomes therefore represent a promising route that avoids the complexity, cost, and regulatory burden associated with cell expansion and extensive laboratory manipulation. Autologous PRP-derived exosomes therefore represent a promising acellular biologic platform with potential for more consistent and scalable products.92–94
Mechanistic and delivery considerations: ED versus PD
In diabetic and CNI models, EV cargo has been shown to engage antioxidant, endothelial-protective, and neurovascular repair programs. For example, EVs enriched with microRNA-200a-3p improved erectile hemodynamics in diabetic rats and were associated with suppression of Keap1 and activation of antioxidant signaling cascades.95 Notably, melatonin-primed MSC-derived small EVs improved erectile recovery after CNI and were linked to enhanced neurovascular repair signaling.96 In addition, pericyte-derived EVs have been associated with microRNA-driven enhancement of endothelial repair in diabetic ED, suggesting that the choice of cell source selection can bias vesicle function toward angiogenic recovery.97 More recently, adipose-derived MSC small EVs were shown to restore erectile physiology after CNI alongside suppression of Galectin-3 and attenuation of oxidative, inflammatory, and profibrotic cascades, supporting Galectin-3 as a plausible therapeutic target for vesicle-based neurovascular repair.98
Compared with living cell delivery, EV therapeutics may offer distinct safety and manufacturing advantages compared with living cell delivery. EVs lack proliferative or differentiative effects, reducing theoretical risks related to ectopic tissue formation or long-term engraftment. Their nanoscale size may further facilitate movement through fibrotic microenvironments that are relatively inaccessible to transplanted cells, a consideration particularly relevant to corporal fibrosis and tunical plaques. In addition, EV cargo can be engineered to enhance potency, and EV surfaces can be modified to improve targeting to specific tissues without introducing living, proliferative products.99,100 Such characteristics strengthen the translational appeal of EVs-based platforms.
Formulation strategies may further enable less invasive delivery routes and may interact with energy-based modalities, although evidence remains exploratory. For instance, glans administration of urine-derived stem cell EVs incorporated within a hyaluronic acid matrix improved erectile outcomes in a diabetic model, suggesting feasibility for mucosal delivery using appropriately engineered formulations.101 Similarly, urine-derived stem cell EVs have been evaluated in combination with microenergy acoustic pulse therapy in experimental ED, and exosomes released from Schwann cells have been implicated in cavernous nerve regeneration after acoustic pulse exposure. These finding supports a model in which local vesicle signaling may contribute to neuromodulatory repair processes.102,103
In PD models, paracrine and EV-based approaches have also shown signals of modulating tunical fibrosis and associated erectile impairment, although the evidence base remains comparatively limited. For example, adipose-derived stem cell therapy was associated with both prevention and treatment of erectile impairment linked to tunical fibrosis in a rat PD model, supporting antifibrotic paracrine activity in addition to corporal repair.104 In addition, intratunical injection of urine-derived stem cell EVs prevented tunical fibrosis and improved erectile function in an experimental PD model.105 A pilot clinical study of intraplaque autologous adipose-derived regenerative cell injections in chronic PD further demonstrated feasibility and provides a foundation for controlled studies that define which disease phenotypes may benefit from cellular versus acellular regenerative strategies.106
Taken together, EVs represent a pivotal bridge between empiric biologics and engineered nanomedicine, combining multi-pathway signaling with an acellular, engineerable product profile.
In this context, EVs represent a pivotal bridge between empiric biologics and engineered nanomedicine, combining multi-pathway signaling with an acellular, engineerable product profile. The determinant of clinical impact is not signal capacity alone, but sustained localization and effective tissue exposure, a requirement that elevates injectable delivery platforms from supportive adjuncts to critical determinants of therapeutic effect.107,108 Accordingly, the following section examines how hydrogels and “smart” injectable systems can provide the spatiotemporal control necessary to improve target engagement in ED and PD.
Hydrogels and smart injectable platforms
Why depots matter: washout versus diffusion barrier
Because durable tissue remodeling depends on sustained local exposure to regenerative or antifibrotic signals, increasing emphasis has been placed on injectable hydrogels and depot platforms that can overcome the pharmacokinetic constraints of penile tissues.109 Cavernosal tissue is highly perfused, and rapid venous outflow can shorten residence time after bolus intracavernosal delivery.110 In PD, plaques are collagen rich and diffusion limited, which can restrict contact with key cellular targets and reduce the likelihood that brief exposure will shift myofibroblast activity or ECM turnover.111 Smart injectable depots address both challenges by forming in situ reservoirs that govern spatial distribution and release kinetics, thereby aligning exposure with the biologic timescale of remodeling rather than rapid clearance intervals.112 These disease-specific delivery barriers are summarized in Figure 2, and the principal PD-specific obstacles to plaque-confined therapy are distilled in Table 2.
Figure 2.
Disease-specific delivery barriers and translational requirements for regenerative biologics in erectile dysfunction and Peyronie’s disease. Conceptual comparison of erectile dysfunction as a high-perfusion washout environment versus Peyronie’s disease as a collagen-dense, diffusion-limited plaque. The schematic highlights strengths and key limitations of platelet-rich plasma, mesenchymal stromal cells, and extracellular vesicles/exosomes, and illustrates how nano-enabled delivery aims to improve retention, targeting, and cellular uptake. The bottom panel summarizes key elements required for clinical translation, including phenotype-enriched trials, credible sham and placebo-mitigating designs, standardized extracellular vesicle characterization and potency assessment (MISEV-aligned), and safety/regulatory readiness. Abbreviations: ED, erectile dysfunction; PD, Peyronie’s disease; PRP, platelet-rich plasma; MSCs, mesenchymal stromal cells; EVs, extracellular vesicles; MISEV, minimal information for studies of extracellular vesicles.
Emerging filtration-based technologies aim to concentrate the platelet secretome while preserving extracellular vesicles and soluble signaling mediators, potentially recreating a broader regenerative microenvironment relevant to both ED and PD.113
Smart injectable platforms encompass in situ-forming depots based on thermosensitive or stimuli-responsive hydrogels, matrix-interactive materials that promote adhesion or collagen binding, and delivery approaches that improve localization and extend residence time after penile administration.114 This definition also includes nano-enabled depots that, while not necessarily nanoscale in their final dimensions, exploit nanoscale engineering to control release kinetics, tissue retention, or cellular uptake.114
Within this broad class, hydrogels represent one of the most extensively investigated smart injectable systems. Hydrogels are three-dimensional, water-absorbing polymer networks that closely mimic key features of the native ECM. Their intrinsic softness, high water content, viscoelasticity, biodegradability, and biocompatibility make them particularly well suited for biomedical applications. In addition, their mucoadhesive and bioadhesive properties enable non-covalent interactions with mucosal and epithelial tissues, enhancing tissue permeability and prolonging local drug residence. Their low interfacial tension with aqueous and biological fluids further minimizes nonspecific cell adhesion and reduces the risk of undesirable immune responses.115
The highly porous and hydrated architecture of hydrogels, together with their tunable physicochemical properties, allows encapsulation and controlled release of a wide spectrum of therapeutic agents, including small molecules, proteins, growth factors, and EVs. As a result, hydrogels can support sustained, localized, or targeted delivery profiles tailored to specific therapeutic needs.115
Penile application imposes stricter design requirements than generic hydrogel use. In ED, the principal objective is to extend corporal exposure without creating a persistent implant effect that alters cavernosal compliance, impairs expansion, or interferes with veno-occlusive function.116,117 In PD, a depot must remain sufficiently localized within or adjacent to the plaque to improve intralesional exposure, yet it must not increase nodularity, stiffen the tunica, or create asymmetric biomechanics that could worsen deformity.118,119 Accordingly, the most relevant hydrogel properties in this field are transient residence, predictable biodegradation, minimal inflammatory reactivity, and mechanical compatibility with the target penile compartment.48
A particularly promising application involves combining injectable hydrogels with PRP to form localized depots that retain platelets and EVs at the injection site while mitigating the rapid burst release of growth factors and cytokines typically associated with PRP administration. By slowing diffusion and degradation, these systems enhance local bioavailability and prolong regenerative signaling. Beyond direct PRP incorporation, hydrogel-based delivery of isolated platelet-derived exosomes has been widely reported in wound healing and tissue regeneration, further underscoring the versatility of these platforms.
To preserve the autologous nature of PRP-based therapies, autologous hydrogel systems can be generated and subsequently combined with PRP. Plasma-derived thermosensitive hydrogels represent a compelling example, as they can be formed from autologous plasma components and undergo temperature-triggered gelation in situ. These plasma gels are particularly effective at retaining platelets and EVs, reducing burst release, and extending local biological activity. Moreover, their autologous origin, native protein composition, and mild thermal processing conditions support exosome stability and biological function without the need for synthetic crosslinkers or chemical modification.120,121
Building on this concept, the combination of plasma gel–based thermosensitive hydrogels with PRP enriched in platelet-derived exosomes, such as PTBM-PRP, could emerge as a highly promising strategy.44 This approach would enable the delivery of high concentrations of bioactive platelet-derived exosomes while preserving intact platelets and their dynamic secretory capacity. Temperature-induced gelation would further enhance tissue retention and sustained release, collectively maximizing therapeutic efficacy in regenerative applications.121–124 A schematic overview of this plasma-derived hydrogel–exosome depot concept is shown in Figure 3. Preclinical models provide initial support for this delivery concept in erectile tissue.
Figure 3.
Example workflow for an autologous plasma-derived hydrogel depot incorporating platelet-derived exosomes. Platelet-poor plasma (PPP) can be processed to form a thermosensitive plasma gel/hydrogel, while platelet-rich plasma (PRP) can be preconditioned to enrich extracellular vesicles/exosomes. Incorporation of exosomes into the plasma gel is intended to create an exposure-modulating depot or scaffold that prolongs local retention and controlled release after injection. Abbreviations: PPP, platelet-poor plasma; PRP, platelet-rich plasma; EVs, extracellular vesicles.
ED models: EV-loaded thermosensitive hydrogels
In rodent CNI models, thermosensitive hydrogels can be administered as liquids and solidify in situ to form local depots, prolonging exposure compared with bolus delivery. In a CNI model, an injectable thermosensitive hydrogel loaded with adipose-derived MSC small EVs was associated with improved functional recovery and attenuation of maladaptive remodeling relative to bolus EV administration.125 Similarly, photoacoustic image-guided intratunical delivery of small EVs within a thermosensitive hydrogel improved erectile recovery and supported endothelial and neuronal restoration in an experimental model.126 Collectively, these findings support a consistent translational principle: EV bioactivity alone may be insufficient to overcome corporal washout unless paired with a material-based delivery strategy that stabilizes local distribution and sustains exposure across the biological relevant remodeling window.
Design levers, targeting, and safety considerations
Material design and spatial control of exposure
Hydrogel design parameters, including polymer chemistry, crosslink density, and degradation triggers, provide controllable levers to tune retention, release kinetics, and mechanical compatibility with penile tissues. Materials can be engineered to approximate local compliance, thereby minimizing discomfort and reducing the risk of foreign-body responses. In ED, this means avoiding durable changes in corporal compliance; in PD, it means avoiding added tunical stiffness, nodularity, or plaque asymmetry. Degradation may be coupled to enzymatic activity or inflammatory cues, enabling release to accelerate in reactive environments while remaining slower in more stable fibrotic tissue. Importantly for PD, hydrogels can incorporate matrix-binding motifs that enhance retention within collagen-rich compartments and support sustained intraplaque exposure where passive diffusion is limited.127
Device-enabled and physically guided delivery approaches offer an additional route to reduce operator dependence and improve localization by stabilizing where the payload resides after injection. Magnetic guidance has been shown to increase retention of injected stem cells within the corpus cavernosum after CNI, demonstrating that physical targeting can mitigate washout and improve local exposure.128 In preclinical rat and beagle models, magnetic soft microrobots enabling magnetically guided intracavernosal MSC delivery increased local retention and were associated with restoration of erectile function.129 Single-cell transcriptomic analyses in this context supported neurovascular regeneration programs linked to enrichment of regenerative macrophage states, suggesting an immunoregenerative component to the observed benefit.129 Conceptually, analogous strategies could be adapted for EV therapy by incorporating magnetic nanoparticles, imaging tracers, or matrix-binding ligands within hydrogels, thereby enabling post-injection localization and standardize exposure across operators and clinical centers.
For PD, EV-loaded hydrogel depots are particularly attractive because they combine multi-component signaling with a localized reservoir that can be placed directly into the diseased tunica. While EVs can modulate fibroblast phenotype, immune signaling, and ECM turnover, bolus intraplaque injection is unlikely to maintain adequate exposure within diffusion-restricted tissue. In contrast, a depot could provide sustained intraplaque EV release over weeks, increasing the likelihood of uptake by plaque-resident fibroblasts and immune cells and aligning therapeutic exposure with the temporal dynamics of matrix remodeling rather than short-lived diffusion and clearance.130,131
Safety and regulatory considerations
Despite their promise, hydrogel depots introduce potential risks that must be addressed before clinical adoption in penile tissues. Material persistence can provoke foreign-body inflammation, and depot mechanics may alter corporal compliance or plaque stiffness if the material is not tailored to the corporal or tunical microenvironment.132,133 From a regulatory perspective, sterility assurance, reproducible gelation kinetics, predictable degradation products, and demonstrable compatibility between biomaterial and payload are essential for combination-product development pathways.133,134 In addition, dose-escalation studies should include systematic monitoring for both procedures and material-related adverse events, such as pain, nodularity, worsening deformity, inflammatory reactions, as well as for any functional consequences related to altered tissue biomechanics.
Beyond injectable depots, scaffold-based approaches also support sustained regenerative signaling by maintaining bioactive cues at the site of disease. For example, a stem cell delivery patch composed of decellularized fibroblast-derived ECM integrated with a biocompatible hydrogel improved erectile outcomes in a bilateral CNI model, supporting tissue-engineering strategies that maintain local regenerative cues at the injury niche.135 Platelet-poor plasma (PPP) has been also used to produce scaffolds, providing a biologically active and structurally stable matrix. Such PPP-based scaffolds can be used with PRP-derived exosomes, enabling sustained release.
Take-home, disease-specific implications
In ED, particularly neurogenic injury models, hydrogel depots have already demonstrated improved erectile recovery by extending EV retention and sustaining regenerative signaling during critical post-injury remodeling periods.125,126 In PD, hydrogel depots may be even more consequential, especially for stable plaques, where the principal translational barrier is diffusion-limited plaque penetration and sustained intralesional target engagement that is difficult to achieve with bolus injection alone.136,137
Targeted anti-fibrotic nanomedicine in Peyronie’s disease
Following discussion of broad regenerative payloads and enabling delivery platforms such as EVs and hydrogel depots, attention now shifts to target-specific antifibrotic nanotherapies for PD.138 PD is well suited to this approach because the lesion is focal, accessible to local delivery, and quantifiable with imaging-based endpoints that can support objective assessment of plaque burden and treatment response.139 Unlike ED, PD also has an established plaque-targeted clinical benchmark—intralesional CCH in appropriately selected stable disease—which provides a practical comparator for new disease-modifying platforms rather than a therapeutic vacuum.28 The focus here is therefore on antifibrotic targets together with carrier design and retention strategies intended to concentrate activity within the plaque microenvironment and extend local residence in collagen-rich fibrotic tissue.140 Several of the concepts discussed in this section remain hypothesis-generating and are grounded primarily in preclinical PD models or extrapolation from non-penile fibrosis indications rather than PD-specific randomized clinical evidence.
Rationale: a focal, measurable fibrotic lesion
PD is an attractive model for targeted antifibrotic nanomedicine because plaques are discrete lesions within the tunica albuginea that are easily accessible by intralesional injection and followed longitudinally. Plaque burden can be quantified by ultrasound and complemented by elastography-based stiffness measures, enabling studies that link local therapy to objective tissue remodeling rather than relying solely on curvature change.141,142 In contrast to systemic antifibrotic therapy, which is often constrained by dose-limiting toxicity, PD provides an opportunity to test plaque-confined exposure at higher local concentrations with minimal systemic distribution.
Antifibrotic targets in PD: validated pathways and emerging candidates
Transforming growth factor-beta signaling as a central driver of tunical fibrosis
Transforming growth factor-beta (TGF-β) is a central profibrotic cytokine family that drives fibroblast activation, myofibroblast differentiation, and ECM accumulation across a wide range of fibrotic diseases. In rodent PD models, inhibition of TGF-β type I receptor signaling (ALK5) has been associated with regression of plaque fibrosis and improvement in curvature. IN-1130, an ALK5 inhibitor, promoted regression of fibrotic plaques and corrected curvature in a rat PD model.143 Vactosertib, an orally bioavailable ALK5 inhibitor, similarly promoted regression of fibrotic plaques in an experimental PD model.144
Clinical feasibility of TGF-β neutralization is supported in non-penile fibrotic disease, but translation to PD remains largely extrapolative and would require plaque-confined delivery. Fresolimumab, a pan–TGF-β neutralizing antibody, demonstrated pharmacodynamic effects and clinical signals in systemic sclerosis, illustrating that TGF-β blockade can be clinically active in fibrotic disorders.145 However, systemic delivery is unattractive for PD, and proposed local deployment strategies, -such as antibody-loaded hydrogels or antibody-functionalized nanoparticles-, should be framed as platform hypotheses until validated in PD models and early-phase safety studies. Because TGF-β family signaling is integral to physiological wound repair, both the timing and the spatial confinement of inhibition within plaques are critical to minimize local impairment of healing and tissue integrity.146
Galectin-3
Galectin-3 (Gal-3) is a mechanistically attractive antifibrotic target, linking innate immune activation to fibroblast profibrotic behavior. Contemporary reviews recognize Gal-3 therapeutic role across inflammatory and fibrotic diseases and summarize ongoing development of inhibitors and biologics.147 In penile disease biology, Gal-3 has been implicated in inflammation and fibrotic remodeling in vascular ED through toll-like receptor 4–associated signaling, supporting its role as a bridge between injury-associated inflammation and tissue stiffening.148 In broader fibrosis contexts, Gal-3 can also participate in TGF-β pathway activation, offering a rationale for targeting it as an upstream amplifier rather than a downstream marker.149 Importantly, clinical translation of Gal-3 inhibition has progressed in pulmonary fibrosis, where the inhaled inhibitor TD139 demonstrated target engagement signals.150 This supports the feasibility of localized Gal-3 blockade in fibrotic tissue, but translation to PD remains unproven, as well as without penile-specific safety assessment.
Connective tissue growth factor (CTGF/CCN2)
CTGF is a downstream amplifier of ECM production and tissue stiffening downstream of multiple profibrotic pathways. The monoclonal antibody FG-3019 (pamrevlumab) demonstrated safety and biological activity signals in an open-label phase 2 study in idiopathic pulmonary fibrosis,151 and a subsequent randomized trial reported efficacy signals supporting CTGF as a targetable fibrosis mediator.152 Preclinical cardiovascular work further indicates that CTGF blockade can limit maladaptive remodeling after myocardial infarction.153 In context of PD, however, CTGF targeting remains conceptual; any translation would require plaque-confined exposure and careful monitoring for local effects on tunical integrity.
Matrix-directed targeting and plaque retention strategies
A defining translational opportunity in PD is the plaque’s collagen-rich ECM, which can be exploited to enhance retention of antifibrotic payloads. Matrix-directed targeting aims to increase the local effective concentration and residence time of a therapeutic agent within fibrotic tissue. Collagen affinity strategies have increased accumulation of anticytokine antibodies at inflamed sites and improved antifibrotic efficacy in pulmonary fibrosis models,127 while collagen-binding nanoparticles have been developed for targeted delivery to fibrotic renal interstitium,154 and collagen-targeted gold nanoparticles have been explore for fibrosis imaging and localization.155 In PD, similar designs could be used to anchor drug carriers within plaques, such that pathway specificity is determined primarily by the payload while minimizing systemic exposure.
Beyond antibody or small-molecule delivery, gene- and vesicle-based approaches have been tested in PD models to directly modulate profibrotic transcriptional programs. Microvesicles engineered to deliver Smad7 suppressed fibroblast differentiation in a PD model and demonstrated enhanced antifibrotic activity compared with unmodified vesicles.156 MicroRNA-29b attenuated tunical fibrosis in an experimental PD model, consistent with direct regulation of matrix gene expression by microRNA programs.157 EV biology intersects with these concepts: as TGF-β exposure can induce fibroblast EV production enriched in TSG-6, that can inhibit myofibroblast transformation by modulating intracellular signaling.158 EV-mimetic nanovesicles have also been used to profile transcriptomic responses in plaque-derived fibroblasts, illustrating how engineered vesicle platforms can interrogate and potentially reshape plaque biology.159
PD offers a unique opportunity for targeted antifibrotic nanomedicine because plaques are focal, accessible, and measurable. However, the evidence base remains uneven across candidate payloads and platforms, and complex targeted systems should still be regarded as hypothesis-generating until validated in PD-specific models and early-phase safety studies. Near-term trials should therefore prioritize achieving plaque-confined exposure of sufficient duration while explicitly accounting for calcification status and plaque phenotype, and they should balance antifibrotic efficacy against preservation of normal wound repair and tunical integrity.118 In practical terms, new platforms are more appropriately developed as adjuncts to, or benchmarked against, existing intralesional standards rather than framed as immediate replacements.
Translational roadmap—from bench to bedside
The emergence of a second wave of biologics, enabled by advances in nanomedicine and controlled delivery platforms, frames a translational roadmap for the future management of ED and PD. This evolution marks a gradual shift from predominantly symptomatic strategies toward biologically driven, disease-modifying approaches, with tissue regeneration emerging as a central translational objective (Figure 4). Despite a strong mechanistic rationale and encouraging preclinical signals, most regenerative and nano-enabled approaches for ED and PD remain preclinical or confined to early-phase clinical study.160 Translation into routine practice will require coordinated solutions that address disease heterogeneity, robust product characterization, standardized delivery, scalable manufacturing, regulatory readiness, and endpoints capable of demonstrating durable biological modification. Importantly, many of these barriers are not unique to sexual medicine but reflect broader translational challenges across regenerative medicine and nanotherapeutics.
Figure 4.
Conceptual translational roadmap illustrating the evolving management of erectile dysfunction and Peyronie’s disease. The figure depicts a gradual shift from predominantly symptomatic, mechanical, and surgical interventions toward biologically driven, disease-modifying strategies, with tissue regeneration highlighted as a central translational objective enabled by advances in biologics, nanomedicine, and delivery platforms.
Disease heterogeneity is a major constraint, but it differs between ED and PD. In ED, mechanistic diversity spans vasculogenic, neurogenic, endocrine, and mixed phenotypes.161 In PD, heterogeneity is driven more by disease phase, plaque geometry, calcification, and concomitant erectile function status than by a single uniform substrate.162 As a result, clinical trials that pool disparate phenotypes are at risk of neutral or misleading outcomes that reflect inadequate stratification rather than true lack of efficacy. ED and PD should therefore not be treated as interchangeable translational problems.
Product characterization and potency assessment
Robust product characterization and potency assessment remain major translational barriers for acellular biologics and nanobiologics. EV preparations vary substantially due to cell source, culture conditions, isolation and storage methods, while the overlapping vesicle subtypes complicates definite identity claims. Consensus guidelines define minimal requirements for EV characterization and reporting, providing a methodological foundation for reproducibility and cross-study comparability.163 However, potency assays that predict in vivo regenerative performance remain a bottleneck, as EVs act through multi-component cargo and multi-pathway signaling. Dose selection therefore remains largely empiric unless linked to validated functional assays that reflect clinically relevant mechanisms such as endothelial repair, neuroprotection, or antifibrotic activity.164
Linking product potency to patient phenotype represents a practical form of personalization that can enhance signal detection and improve clinical trial efficiency. Biologics with a neurovascular repair dominant activity profile are most logically evaluated in neurogenic ED, whereas an antifibrotic dominant activity profile is more appropriately tested in vasculogenic ED and PD patients. This deliberate alignment between mechanism of action, potency readouts, and clinical phenotype supports interpretable early-phase development and strengthens the rationale for phenotype enriched trial designs in regenerative sexual medicine.165,166
Delivery standardization and dosing
Beyond defining what is delivered, translation requires standardization of how therapies are administered. Image guidance may improve localization but is not yet standardized across protocols, limiting reproducibility between centers.167,168 Smart injectable platforms can reduce operator dependence by forming in situ depots within predefined tissue planes and stabilizing local distribution after injection. However, combination products introduce additional quality attributes that must also be controlled, including gelation kinetics, degradation products, and interactions between biomaterial and biological payload.167,168
Dosing should be conceptualized in terms of target engagement over time, rather than simply injected volume or vesicle count. For EVs and other multi-component biologics, dose selection is most defensible when tied to validated potency metrics and exposure assumptions (eg, depot persistence, retention, and release kinetics), rather than to particle number alone.169
Manufacturing scalability and quality control
Scaling production is another major barrier. Autologous therapies minimize immunologic risk but introduce donor variability and logistical complexity. Allogeneic EVs and engineered nanovesicles offer scalable production and off-the-shelf clinical deployment, but they require rigorous immunologic, stability, and sterility testing. Engineering approaches, including microfluidic production and EV-mimetic nanovesicle generation, are attractive but must demonstrate reproducibility, purity, and functional consistency across lots to satisfy regulatory expectations.170,171
Safety and regulatory considerations
Safety characterization for penile nanomedicine is largely extrapolated from broader biomaterials and nanomedicine experience. Nanomaterials may persist within target tissues or trigger innate immune activation, and EV products may carry bioactive cargo that influences coagulation, inflammation, or unintended tissue pathways.172–174 In the context of penile delivery, depot systems and injectable biomaterials raise additional concerns regarding foreign-body response, progression of tunical or corporal fibrosis, and localized compartment effects that may alter cavernosal compliance or tunical mechanics.175,176
Sustained-release vasodilator depots or high-bioactivity formulations warrant cautious monitoring for clinically meaningful hemodynamic perturbation. Long-term persistence of inorganic nanomaterials, if used, requires dedicated biodistribution and clearance assessment to exclude chronic inflammatory or fibrotic sequelae.177
Immunogenicity with repeated dosing is a further concern for allogeneic EV products and antibody-functionalized nanoparticles. Where repeated administration is planned, immunogenicity should be assessed with anti-product antibody surveillance and monitoring for systemic or local inflammatory responses in both preclinical development and long-term clinical follow-up.178 Early-phase development benefits from prespecified release criteria and robust comparability plans, as even modest manufacturing changes can materially alter cargo composition, impurity profiles, and tissue exposure.178 Ethically, clinicians and investigators should transparently communicate uncertainty of benefit, placebo susceptibility of procedure-based interventions, and the importance of regulated manufacturing and trial oversight, particularly in light of the growing commercial availability of unregulated “regenerative” injections.53
Endpoints and placebo mitigation
Endpoint selection is critical to demonstrate true regenerative effects, particularly because patient-reported outcomes are susceptible to placebo effects, concomitant pharmacologic facilitation, and psychosexual context.
Erectile dysfunction
In early-phase ED trials, efficacy assessment should emphasize durability of response and objective evidence of tissue-level recovery. Durability of erectile function should be evaluated after a prespecified washout from phosphodiesterase type 5 inhibitors (PDE5is), typically longer than 1 month. Penile color duplex Doppler ultrasound performed after standardized intracavernosal stimulation and redosing to achieve complete smooth muscle relaxation is able to quantify arterial inflow and veno-occlusive competence, providing objective hemodynamic characterization. These objective measures should complement patient-reported outcomes, including the erectile function domain of the International Index of Erectile Function, interpreted using prespecified responder definitions and clinically meaningful thresholds, such as Minimal Clinically Important Difference (MCID).179–181
Placebo mitigation is essential in ED trials, as clinically meaningful improvements can occur in placebo arms and contextual effects are amplified in procedure-based interventions. Trial design should incorporate credible sham procedures when feasible and should standardize counseling and contact intensity across arms, since expectation management can influence reported outcomes.182,183 Protocols should also prespecify handling of concomitant PDE5is use, rehabilitation strategies, and counseling interventions to minimize confounding and strengthen attribution of observed effects to the investigational product.
Peyronie’s disease
For early-phase PD trials, endpoints should capture both geometric correction and biological remodeling. Curvature change should be assessed using standardized documentation of erect deformity. Patient-centered outcomes should quantify penetrative feasibility and symptom bother using validated instruments such as the Peyronie’s Disease Questionnaire.184 Plaque characterization should include imaging-based documentation of plaque dimensions and calcification status using penile ultrasonography and, where available, elastography.139,185 Because spontaneous evolution and treatment responsiveness differ by disease phase, enrollment should be stratified using prespecified criteria that define active versus stable disease. Curvature changes should be documented at prespecified intervals.186
Placebo mitigation should be embedded in trial design because procedure-based interventions and expectation effects can inflate subjective outcomes. Rigorous blinding should be implemented when feasible. Concomitant mechanical adjuncts such as traction therapy or vacuum devices should be standardized across study arms to avoid differential co-intervention effects.187,188 Placebo-controlled intralesional trials illustrate the importance of these design elements for interpretable efficacy signals.189
Εxploratory trial design checklist for early-phase studies
The following considerations are presented as a framework for early-phase translational investigation rather than as clinical guidance. Their purpose is to illustrate how mechanism, disease phenotype, and delivery strategy may be aligned in exploratory studies of regenerative biologics and nano-enabled platforms. Any such study design would require trial-grade, well-characterized products, standardized administration procedures, prespecified release criteria, and rigorous safety oversight.
Erectile dysfunction: mechanism-aligned exploratory trial designs
In ED, early translational studies will likely be most informative when enrollment is restricted to phenotypes with relatively coherent injury biology. Post-prostatectomy neurogenic ED represents one such setting, as CNI is followed by a recognizable sequence of corporal hypoxia, smooth muscle depletion, and fibrotic remodeling. Diabetes-associated vasculometabolic ED also remains a rational target because endothelial dysfunction, oxidative stress, microvascular injury, and progressive corporal fibrosis are central to its pathobiology.190–192 By contrast, studies that enroll biologically heterogeneous populations may dilute mechanistic signal, reduce interpretability, and obscure true treatment effects in explanatory studies.
From a delivery perspective, exploratory protocols may examine whether local exposure can be prolonged by pairing intracavernosal biologic administration with a transient slow-release carrier, such as a thermosensitive hydrogel.193 The rationale for this approach is not simply formulation convenience, but the possibility of reducing rapid corporal washout and aligning local bioavailability with the longer time course of tissue repair and remodeling. In this setting, the principal question is whether sustained local exposure can be achieved without creating persistent material effects that alter cavernosal compliance or interfere with normal erectile hemodynamics.
Dose exploration should be linked, as far as possible, to biologically meaningful measures rather than empirical repetition alone. In early-phase studies, this may include potency-informed dosing logic together with objective signals of target engagement, such as standardized penile duplex Doppler parameters obtained after uniform pharmacostimulation.194 When repeat administration is considered, the interval should be justified as an exploratory design choice grounded in the temporal biology of post-injury remodeling rather than presented as an optimized schedule.195
Background penile rehabilitation requires similar caution in design. Because rehabilitation may independently affect oxygenation, smooth muscle preservation, and recovery trajectory, co-interventions should be standardized and prespecified across study arms.193,196 Without such control, interpretation becomes difficult, particularly when modest improvements are attributed to investigational therapy in the setting of variable concomitant rehabilitation.
For outcomes, early studies are better positioned to emphasize feasibility, safety, and preliminary biological activity than definitive efficacy. Surveillance should therefore include pain, inflammation, and procedure-related adverse events,197,198 while secondary efficacy signals may incorporate patient-reported erectile function together with objective vascular readouts.199 Any functional endpoint should ideally be assessed after a prespecified PDE5is washout, so that transient pharmacologic support is not mistaken for a disease-modifying effect.
Peyronie’s disease: plaque-directed exploratory designs
In PD, translational development is more plausibly directed toward plaque-confined adjunctive or comparator strategies than toward replacement of established intralesional treatments.14 The biological and mechanical features of the plaque create a distinct delivery problem, and this has implications for both phenotype selection and endpoint choice. Earlier inflammatory or remodeling-active phases may offer a more permissive setting for immunomodulatory or antifibrotic intervention, whereas stable disease may require prolonged plaque-localized exposure if extracellular matrix composition or tissue stiffness is to be meaningfully influenced.14 Noncalcified or less densely calcified plaques may therefore represent more informative substrates for early proof-of-mechanism studies.168 Such phenotype-enriched designs may increase the likelihood of detecting biologically meaningful signals in early-phase trials.
With respect to delivery, plaque-directed systems are best framed as experimental platforms intended to increase local target engagement within fibrotic tissue. Hydrogel depots, matrix-anchoring approaches, and related retention-enhancing strategies may be useful in this context if they improve residence within or adjacent to the plaque without increasing nodularity, tunical stiffness, or asymmetric biomechanics.127 The central translational issue is not simply whether an antifibrotic payload can be delivered, but whether it can be confined to the plaque environment in a manner that is biologically meaningful and mechanically well tolerated.
Pathway-directed approaches targeting transforming growth factor beta signaling remain conceptually attractive because of their relevance to fibrotic remodeling, and preclinical Peyronie’s models have provided support for this direction.143 Other fibrosis-associated nodes, including galectin-3 and connective tissue growth factor, may also warrant consideration.150 At present, however, such candidates are most appropriately described as translational extrapolations rather than validated therapeutic directions in PD. Their relevance will depend on confirmation in disease-specific penile models and on early penile safety data demonstrating that local intervention does not adversely affect tunical structure or healing.200
Staged or sequential release concepts may also be explored, particularly where the biological objective is to influence evolving plaque activity over time. Even so, choices regarding depot composition, release sequence, or retreatment interval should be presented as hypothesis-generating design variables rather than protocol recommendations.14 In this disease, over-specification risks making an exploratory framework read like practice guidance.
Endpoints in PD should also extend beyond mechanical straightening alone. Curvature remains clinically important, but a more convincing signal of biological remodeling would include concordant changes in plaque burden, stiffness, or imaging-defined characteristics, ideally accompanied by improvement in penetrative function and patient bother using validated instruments.184,185 Isolated changes in curvature, particularly over short observation periods, may be difficult to distinguish from measurement variability or the natural fluctuation of symptoms.
Safety monitoring warrants particular emphasis because many antifibrotic pathways also participate in normal tissue repair.146 Early studies should therefore include predefined stopping criteria and structured surveillance for worsening pain, new nodularity, progression of deformity, or imaging features suggesting adverse remodeling.200 In PD, tolerability cannot be separated from biomechanics; a formulation that achieves local retention but increases plaque stiffness or tunical asymmetry would not represent successful translation.
Cross-cutting trial design principles
Across both ED and PD, early clinical investigation is likely to be most informative when it remains mechanism-informed, phenotype-enriched, and anchored to measurable evidence of local biological target engagement.24,200 Standardized delivery methods, imaging-supported biomarkers, and careful control of co-interventions are essential if biological signal is to be distinguished from placebo response, background therapy, or natural history. Comparative effectiveness questions are more appropriate addressed in later stages of development.24,27,201 At the present stage, the more immediate aim is to determine whether a given biologic-platform combination can be delivered reproducibly, safely tolerated, and linked to credible mechanistic activity in the relevant penile compartment.
Accordingly, these study concepts are best framed as a trial design checklist for hypothesis-generating early-phase research rather than as future treatment protocols. Such positioning more accurately reflects the current maturity of the field and preserves an appropriate distinction between exploratory translational design and clinical recommendation.
Conclusions
The field is no longer defined solely by biologic plausibility, but it remains unevenly mature across ED and PD. For ED, clinically effective disease modification is still unproven; the clearest advance has been a conceptual shift from empiric PRP and cell injections toward acellular, engineerable platforms designed to overcome corporal washout and extend neurovascular target engagement. For PD, the field is further along in that CCH already provides a minimally invasive plaque-targeted clinical benchmark in selected stable disease, even though it does not fully normalize plaque biology or overcome calcified, diffusion-limited substrates.
In the short term, the most credible progress is likely to come from better alignment of mechanism, phenotype, and delivery rather than from increasingly complex payloads alone. For ED, phenotype-enriched studies in post-prostatectomy neurogenic and diabetes-associated vasculometabolic disease, coupled with sham-aware design and objective hemodynamic endpoints, are the most plausible route to interpretable efficacy signals. For PD, the near-term opportunity lies in plaque-confined delivery strategies—potentially adjunctive to or benchmarked against current intralesional therapy—that are tested in clearly defined active or stable phenotypes with imaging-based assessment of plaque size, stiffness, and calcification.
Over the longer term, disease modification will depend on platforms that combine standardized potency, reproducible manufacturing, and anatomy-matched exposure control. Hydrogels, matrix-interactive materials, and targeted nanocarriers may provide this framework by stabilizing spatial distribution in ED and improving intraplaque persistence in PD, while EV engineering and pathway-directed antifibrotics may sharpen biological specificity. Translation, however, will require durable safety data, scalable combination-product manufacturing, and regulatory pathways that can support repeated local administration.
Overall, regenerative sexual medicine is entering a more disciplined second wave. Success will depend less on the novelty of the biologic alone and more on whether the chosen payload, delivery platform, disease phenotype, and endpoint strategy are aligned with sufficient rigor to demonstrate true tissue-level modification. This emerging paradigm may be viewed as exposure-controlled regenerative therapy, in which sustained target engagement within the penile tissue compartment becomes the central determinant of biological effect. If these elements converge, regenerative strategies may move from experimental promise toward clinically meaningful disease modification in ED and PD.
Appendix. Search Transparency for the Narrative Review
This appendix is provided to improve reproducibility of the narrative review and should not be interpreted as PRISMA-compliant systematic-review reporting.
PubMed/MEDLINE search string
(“erectile dysfunction”[Title/Abstract] OR “Peyronie’s disease” [Title/Abstract] OR “penile fibrosis”[Title/Abstract]) AND (“regenerative therapy”[Title/Abstract] OR “platelet-rich plasma”[Title/Abstract] OR PRP[Title/Abstract] OR “stem cells”[Title/Abstract] OR “mesenchymal stromal cells”[Title/Abstract] OR “extracellular vesicles”[Title/Abstract] OR exosomes[Title/Abstract] OR nanomedicine [Title/Abstract] OR nanoparticles[Title/Abstract] OR hydrogels[Title/Abstract] OR “drug delivery”[Title/Abstract]) AND (“2000/01/01”[Date - Publication]: “2025/03/31”[Date - Publication]) AND english[Language].
Staged narrative selection framework
Because exact record-level flow was not prospectively captured, the staged framework below summarizes how studies were identified and synthesized without implying systematic-review conduct.
| Stage | Operational description |
|---|---|
| Identification | Retrieve records from PubMed/MEDLINE, Embase, and Web of Science using disease, fibrosis, regenerative, and delivery-related concepts. |
| Topical triage | Exclude clearly irrelevant records and duplicate concepts during initial review of titles, abstracts, and citation lists. |
| Eligibility review | Review full text when a study addresses ED or PD together with regenerative biologics, nano-enabled delivery, tissue remodeling, or mechanistic relevance. |
| Qualitative abstraction | Extract study design, platform type, route of administration, target compartment, mechanistic rationale, outcomes, durability, and safety signals. |
| Narrative synthesis | Organize included evidence by disease (ED vs PD), payload class, delivery barrier, and translational readiness, with iterative backward citation searching for key papers. |
Contributor Information
Aris Kaltsas, Third Department of Urology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece.
Dimitrios Hatzichristou, Institute for the Study of Urological Diseases and Center for Sexual and Reproductive Health, 54622 Thessaloniki, Greece.
Author contributions
Aris Kaltsas, Dimitris Hatzichristou: Conceptualization, Methodology, Resources, Writing—review and editing, Visualization, Aris Kaltsas: Writing—original draft preparation, Dimitris Hatzichristou: Supervision. All authors have read and agreed to the published version of the manuscript.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflicts of interest
None declared.
Data availability
not applicable.
Ethics approval/consent
not applicable.
Registration
not applicable.
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Data Availability Statement
not applicable.