Published online Oct 15, 2026. doi: 10.4239/wjd.123286
Revised: July 11, 2026
Accepted: September 4, 2026
Published online: October 15, 2026
Processing time: 152 Days and 1.3 Hours
Painful diabetic neuropathy (PDN) affects 15%-26% of individuals with diabetes mellitus and remains one of the most common yet therapeutically challenging chronic pain complications. Current first-line treatments, including pregabalin, duloxetine, gabapentin, and tricyclic antidepressants, provide symptomatic relief for only a subset of patients and do not modify the underlying disease process. PDN is driven by chronic hyperglycemia-induced metabolic dysfunction, Sch
Core Tip: Exosomes play a central role in painful diabetic neuropathy (PDN) by mediating pathological intercellular signaling while also serving as promising therapeutic vehicles targeting neuroinflammation, axonal degeneration, and pain sensitization. Circulating exosomal microRNA and protein signatures are promising candidate biomarkers, but their clinical application is currently limited by the lack of standardized reference ranges, unresolved specificity across diabetic complications, and confounding effects of diabetic nephropathy, requiring validation in large prospective studies. Likewise, mesenchymal stem cell-derived and engineered exosomes demonstrate robust therapeutic efficacy and neuroprotective effects in preclinical PDN models; however, no clinical trials have yet evaluated these approaches in PDN patients, underscoring the need for clinical translation before they can be considered disease-modifying therapies.
- Citation: Long I, Abdo Qaid EY. Exosomes as emerging mediators and therapeutic vehicles in painful diabetic neuropathy: From pathophysiology to clinical translation. World J Diabetes 2026; 17(10): 123286
- URL: https://www.wjgnet.com/1948-9358/full/v17/i10/123286.htm
- DOI: https://dx.doi.org/10.4239/wjd.123286
Diabetes mellitus constitutes one of the most consequential global health challenges of the twenty-first century, with the International Diabetes Federation estimating 537 million affected adults in 2021, a number projected to surpass 780 million by 2045[1]. Among the spectrum of long-term diabetic complications, peripheral neuropathy stands as the most prevalent, affecting up to 50% of individuals over the disease course[2]. Within this category, painful diabetic neuropathy (PDN), characterized by spontaneous burning pain, allodynia, hyperalgesia, and paresthesia in a length-dependent distribution predominantly affecting the distal lower extremities, afflicts 15%-26% of diabetic patients worldwide, imposing a profound burden on quality of life, sleep, mobility, and mental health[3].
Despite this enormous disease burden, the therapeutic landscape remains critically inadequate. Major international guidelines recommend pregabalin, duloxetine, gabapentin, and tricyclic antidepressants as first-line pharmacological options[4]. These agents achieve clinically meaningful pain reduction in only 30%-50% of treated patients, carry dose-limiting adverse effects including somnolence, dizziness, and weight gain, and critically exert no demonstrable neuroprotective or nerve-regenerating effect[5]. The biological cascade of neurodegeneration proceeds unchecked under current therapy, creating an urgent and unmet need for disease-modifying interventions.
Diabetic peripheral neuropathy (DPN) is the most common chronic complication of diabetes, affecting up to 50% of individuals during the course of the disease, with approximately one-third to one-half developing PDN, a condition that markedly impairs physical function, sleep quality, and quality of life. Despite its high prevalence, currently available treatments remain largely symptomatic and do not halt progressive axonal degeneration or promote nerve regeneration. Recent clinical evidence, including a phase 2a trial of topical pirenzepine, has demonstrated that structural regeneration of intraepidermal nerve fibers is achievable in patients with DPN, highlighting the growing shift toward disease-modifying therapies rather than symptom control alone[6].
The pathophysiology of PDN is multidimensional, encompassing chronic hyperglycemia-driven metabolic insults, polyol pathway activation, advanced glycation end-product (AGE) accumulation, mitochondrial dysfunction, oxidative stress, alongside sustained neuroinflammation, progressive Schwann cell dysfunction, axonal degeneration with loss of intraepidermal nerve fiber density (IENFD), and maladaptive central sensitization in the spinal dorsal horn[7,8]. This mechanistic complexity demands therapeutic and diagnostic strategies capable of operating simultaneously across multiple biological levels.
At the same time, growing evidence indicates that diabetic neuropathy is driven by complex interactions among metabolic dysfunction, oxidative stress, neuroinflammation, mitochondrial impairment, Schwann cell dysfunction, and microvascular injury rather than hyperglycemia alone. This multifactorial pathophysiology partly explains the limited efficacy of conventional single-target pharmacotherapies and supports the investigation of biological platforms capable of simultaneously modulating multiple pathogenic pathways.
Exosomes have therefore emerged as attractive candidates because they participate directly in intercellular com
While previous reviews have broadly discussed exosomes in neuropathic pain or diabetic complications, none has comprehensively integrated their pathogenic, diagnostic, and therapeutic roles specifically in PDN, where peripheral nerve injury and central sensitization coexist[11-13]. Recent advances[14-16] in engineered exosomes and exosomal miRNA biomarkers (e.g., miR-21-5p, miR-146a-5p, and the let-7 family) further justify an updated synthesis of this rapidly evolving field[17-20]. This review therefore provides a timely, scoping-based integration of current evidence to identify key translational opportunities and knowledge gaps.
This review includes both preclinical and human studies, although the evidence is predominantly derived from animal models because no clinical trials have evaluated exosome-based therapies in PDN. Human evidence[4,15,16] is limited to biomarker studies, a single mesenchymal stem cell (MSC)-derived exosome trial in diabetic foot ulcer patients, and clinical data on approved PDN therapies[17-21]. Throughout the review, preclinical findings are clearly distinguished from clinical evidence, and translational conclusions are interpreted accordingly.
Converging evidence from cell culture, animal, and human biospecimen studies have illuminated the dual role of exosomes in PDN. Under conditions of hyperglycemia, oxidative stress, and inflammatory activation, exosomes carry pathological cargo that propagates nerve injury and amplifies neuroinflammation[10]. Conversely, exosomes derived from MSCs and other therapeutically competent populations possess potent neuroprotective, anti-inflammatory, pro-regenerative, and analgesic properties demonstrated in preclinical models of diabetic neuropathy[11,12]. Their natural capacity to traverse the blood-nerve and blood-brain barriers (BBB), combined with intrinsic biocompatibility, low immunogenicity, and amenability to surface engineering, renders exosomes uniquely suited as both diagnostic tools and therapeutic platforms.
This review provides a comprehensive synthesis of the pathogenic, diagnostic, and therapeutic roles of exosomes in PDN. By integrating evidence from both preclinical and human studies while clearly distinguishing established clinical findings from preclinical evidence, it offers a balanced assessment of the current translational readiness of exosome-based diagnostic and therapeutic strategies and highlights the key challenges for future clinical applications.
This review was conducted as a scoping review following the five-stage methodological framework of Arksey and O’Malley, as subsequently refined by the Joanna Briggs Institute. Reporting adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist[22]. A scoping review design was selected, given the broad and mechanistically diverse nature of the evidence base spanning pathogenesis, biomarker development, and therapeutic application, and the need to map the scope and distribution of available evidence rather than synthesize pooled effect estimates. Consistent with scoping review methodology, the evidence presented in subsequent chapters is synthesized narratively rather than as a purely tabulated evidence map. This approach was adopted because the review aims not only to map the available evidence but also to illustrate the mechanistic relationships between exosome biology, PDN pathophysiology, biomarker development, and therapeutic applications. Accordingly, the narrative synthesis integrates findings across these domains while maintaining transparent evidence mapping through Tables 1, 2, 3, and 4 and Figure 1. This approach aligns with Joanna Briggs Institute guidance, which supports descriptive analytical synthesis in scoping reviews without quantitative pooling of effect estimates. Throughout the review, descriptive evidence is clearly distinguished from interpretive discussion, and key translational knowledge gaps are highlighted below.
| Category | Mechanism/component | Pathways and molecular mediators | Pathological consequences | Functional/clinical correlates | Synthetic insight: Cross-mechanism interaction and therapeutic implication |
| Peripheral mechanisms of nerve injury | Polyol pathway activation | Aldose reductase (glucose → sorbitol); sorbitol dehydrogenase (sorbitol → fructose); NADPH depletion; NADH generation | Osmotic stress; myo-inositol depletion; impaired Na+/K+-ATPase; reduced glutathione; mitochondrial superoxide production | Increased oxidative stress; axonal dysfunction; reduced antioxidant capacity | Represents the earliest measurable metabolic insult; NADPH depletion directly links polyol pathway activation to downstream mitochondrial dysfunction (row below) by impairing glutathione regeneration. Exosomal cargo from metabolically stressed neurons under polyol pathway activation is the proposed upstream trigger for Schwann cell exosomal reprogramming (Table 2) |
| AGEs | Non-enzymatic glycation by methylglyoxal; RAGE activation; NF-κB signaling | Direct structural modification of myelin and cytoskeletal proteins; accelerated protein degradation; chronic sterile neuroinflammation | Progressive protein dysfunction; sustained inflammatory state; Schwann cell, endothelial cell, and macrophage activation | AGE/RAGE activation provides the mechanistic bridge between chronic hyperglycemia and sustained neuroinflammation; RAGE activation on Schwann cells directly reprograms their exosomal secretome (Table 2) toward a pro-inflammatory, neurotrophic-depleted profile, linking metabolic and inflammatory pathological arms | |
| Mitochondrial dysfunction | Impaired oxidative phosphorylation; reduced ATP; increased ROS; PGC-1α suppression; excessive mitochondrial fission | Reduced neuronal viability; impaired axonal transport; intrinsic apoptosis pathway activation; nitration/inactivation of mitochondrial enzymes | Energy failure in DRG neurons; progressive distal axonopathy; impaired nerve regeneration | Mitochondrial dysfunction in DRG neurons is both a downstream consequence of polyol/AGE pathology and an independent amplifier; impaired axonal transport reduces retrograde neurotrophic signaling to Schwann cells, accelerating their phenotypic reprogramming and exosomal cargo shift. MSC-derived exosomes carrying HSP70/90 and SIRT1 specifically target this node (Table 5) | |
| Axonal degeneration and demyelination | Progressive IENFD loss; Schwann cell phenotypic transition | Release of MMPs; pro-inflammatory cytokine secretion; altered Schwann cell exosomal cargo (pro-inflammatory miRNAs, depleted neurotrophic factors) | IENFD loss correlates with pain severity and diabetes duration; predominant vulnerability of small unmyelinated C-fibers and thinly myelinated A-delta fibers | IENFD reduction is the structural readout integrating all upstream metabolic and inflammatory insults; its correlation with exosomal miR-21-5p and NfL levels (Table 3) positions it as the primary composite endpoint bridging mechanistic and diagnostic domains, and its reversibility in response to MSC-derived exosome therapy (35%-80% recovery; Table 5) makes it the most relevant disease-modification endpoint for future clinical trials | |
| Peripheral nociceptor sensitization | Voltage-gated sodium channels (Nav1.7, Nav1.8, Nav1.9); TRP channels (TRPV1, TRPA1); HCN channels; potassium channel subtypes | Lowered action potential threshold; increased spontaneous ectopic discharge from injured axons and DRG; channel upregulation and sensitization in neuroinflammation/oxidative stress | Thermal hyperalgesia; mechanical allodynia; spontaneous burning pain | Nav1.7 upregulation and TRPV1 sensitization are directly regulated by Schwann cell-derived exosomal let-7 downregulation and ceramide/sphingosine-1-phosphate delivery (Table 2), mechanistically connecting the glial exosomal secretome to nociceptor hyperexcitability; exosomal let-7a mimic and anti-TRPV1 siRNA therapies (Table 5) specifically target this node without systemic cardiac conduction side effects | |
| Neuroinflammation | Macrophages | Transition from M2-like to M1-like phenotype; RAGE activation; TLR4 signaling | The iNOS upregulation; enhanced TNF-α, IL-1β, IL-6, IL-18; increased matrix metalloproteinase secretion | Degradation of extracellular matrix; Schwann cell dysfunction; axonal degeneration; nociceptor sensitization | M1 macrophage polarization and Schwann cell pathology form a bidirectional feed-forward loop mediated by exosomal miR-155/SOCS1/JAK-STAT signaling (Table 2); this loop, once established, is self-sustaining independently of glycemic level, which may explain why PDN symptoms persist after glycemic control is achieved |
| Schwann cells | Hyperglycemia-induced phenotypic reprogramming; p38 MAPK activation | Reduced NGF, NT-3, BDNF; upregulation of MCP-1 and TNF-α; altered exosomal repertoire (pro-inflammatory miRNAs, depleted neurotrophic cargo) | Impaired neurotrophic support for small-diameter sensory fibers; direct nociceptor sensitization; exosome-mediated propagation of inflammatory signals | Schwann cell exosomal cargo remodeling is the central pathogenic hub connecting vascular injury (endothelial exosomal dysfunction), metabolic stress (AGE/mitochondrial pathway), macrophage activation, and peripheral nociceptor sensitization; it is therefore also the primary target of MSC-derived exosome therapy (Table 5), which restores the physiological Schwann cell exosomal phenotype | |
| SGCs | Reactive phenotype in response to peripheral nerve injury and inflammatory signals | Increased GFAP, connexin 43; IL-1β, TNF-α production | Paracrine inflammatory microenvironment within DRG; lowered excitability threshold of sensory neuron somata; promoted ectopic discharge; sustained peripheral sensitization | SGC activation amplifies peripheral sensitization by lowering DRG neuron excitability thresholds via connexin 43-mediated gap junctions; this mechanism is currently underrepresented in exosomal biomarker panels (Tables 3, 4 and 7) and represents a significant gap in the PDN exosome literature | |
| Endoneurial vasculature | Dysregulation of vasa nervorum; blood-nerve barrier disruption | Altered exosomal cargo (pro-coagulant factors); impaired tight junction integrity | Facilitated macrophage infiltration; entry of systemic inflammatory mediators into endoneurial compartment | Vascular injury is the earliest initiating node in the pathological cascade (Table 2), upstream of Schwann cell and macrophage pathology; adipose-derived MSC exosomes with pro-angiogenic VEGF/miR-132-3p cargo (Table 5) specifically target this node, but are expected to only partially attenuate downstream pathology occurring through vasculature-independent routes | |
| Central sensitization | Spinal dorsal horn synaptic plasticity | Wind-up and long-term potentiation at C-fiber synapses; NMDA receptor activation; substance P; CGRP; neurokinin-1 receptor | Calcium influx; post-synaptic kinase activation; immediate early gene expression; synaptic structural remodeling | Sustained enhancement of synaptic efficacy; transition to sensitized central state | Spinal LTP at C-fiber synapses has been directly demonstrated in STZ-diabetic rodent models; however, the contribution of peripherally derived pathological exosomes to this process (Table 2) remains inferential and has not been directly demonstrated in PDN models – distinguishing it from the better-evidenced peripheral mechanisms above |
| Spinal microglia | Activation via ATP (P2X4, P2X7), fractalkine (CX3CR1), CSF-1; BDNF release | BDNF → TrkB → KCC2 (reduce) → converts GABAergic inhibition into net excitation | Loss of inhibitory tone; enhanced nociceptive transmission; central disinhibition | Microglial BDNF/KCC2 suppression is the most directly evidenced central sensitization mechanism in PDN models and the most tractable central exosomal therapeutic target; IL-4-stimulated macrophage exosomes enriched with IL-10, TGF-β, and miR-124 restore KCC2 expression in diabetic rodent spinal cord (Table 5) | |
| Spinal astrocytes | Activation; downregulation of GLT-1, GLAST | Reduced GLT-1/GLAST expression; glutamate spillover; D-serine and TNF-α release; extrasynaptic NMDA receptor activation | Potentiated synaptic transmission; sustained central sensitization | Astrocytic GLT-1/GLAST downregulation by exosomal miRNAs has been demonstrated in general neuroinflammatory models but not specifically in PDN spinal cord tissue; this mechanistic inference requires direct PDN-model confirmation before astrocyte-targeting exosomal therapies can be rationally designed | |
| Descending pain modulatory system | Impaired descending inhibition (reduced noradrenaline, reduced alpha-2 adrenergic receptors); enhanced descending facilitation (increased 5-HT on 5-HT3 receptors) | Imbalance between descending inhibition and facilitation; permissive central environment for pain amplification | Allodynia and hyperalgesia; pain signals amplified rather than gated; largely refractory to peripherally targeted analgesics | Descending modulatory pathway dysfunction explains the frequent inadequacy of peripherally targeted therapies in PDN and creates the strongest mechanistic rationale for intranasal exosomal delivery strategies capable of accessing supraspinal pain-modulatory circuits; however, direct exosomal evidence for this pathway in PDN is currently absent |
| Exosome source | Condition/stimulus | Altered exosomal cargo | Pathophysiological consequence | Mechanism of action | Temporal sequence/position in cascade |
| Hyperglycemia-exposed cells (general) | Chronic hyperglycemia, oxidative stress | Increased nSMase2, increased ESCRT components | Exosomal hypersecretion; increased burden of pathologically conditioned vesicles | Ceramide-dependent and ESCRT-dependent pathway activation | Foundational/upstream node – establishes the generalized hypersecretory state permissive for all downstream cell-specific cargo remodeling below |
| Endothelial cells (vasa nervorum) | Hyperglycemic injury | Increased pro-coagulant phosphatidylserine, tissue factor, von Willebrand factor; oxidized LDL, asymmetric dimethylarginine; miRNAs targeting eNOS | Hypercoagulable endoneurial milieu; impaired NO bioavailability → vasoconstriction; pericyte apoptosis; blood-nerve barrier disruption | Transfer of pro-apoptotic proteins and miRNAs targeting claudin/occludin | Early/initiating node – precedes measurable Schwann cell cargo shift and macrophage accumulation in diabetic rodent models; proposed upstream trigger of Schwann cell and macrophage pathology (below) via endoneurial hypoxia and barrier breakdown |
| Schwann cells (physiological) | Normoglycemia | NGF, BDNF, NT-3, GDNF; pyruvate, lactate; myelin proteins/Lipids | Axonal trophic support, metabolic substrate delivery, myelin maintenance | Exosomal transfer of neurotrophins and metabolic fuels to axons | Baseline/reference state – homeostatic phenotype contrasted against the hyperglycemic Schwann cell shift below |
| Schwann cells (hyperglycemic) | High glucose exposure | Reduced NGF, BDNF, HSP70; increased cleaved caspase-3, Bax, oxidized proteins; increased miR-21-3p, miR-28-3p, miR-34a | Loss of neuroprotection; axonal degeneration; intraepidermal nerve fiber loss; mechanical allodynia, thermal hyperalgesia | Delivery of pro-apoptotic cargo; targeting pro-survival pathways in axons | Secondary/amplified node – driven directly by hyperglycemia and further intensified by upstream endothelial-derived hypoxia and barrier breakdown (rate-amplifying cofactor, not obligate trigger) |
| Schwann cells (hyperglycemic) | High glucose exposure | Increased miR-let-7 (downregulation of HMGA2 repressor); ceramide, sphingosine-1-phosphate | Nav1.7 and TRPV1 upregulation in sensory neurons; peripheral nociceptor hyperexcitability | MiRNA transfer targeting channel repressors; p38 MAPK/ERK activation → channel phosphorylation/translocation | Secondary/parallel node — co-occurs with the apoptotic cargo shift above; nociceptor-sensitizing arm of the same hyperglycemia-driven Schwann cell reprogramming |
| Classically activated macrophages (M1) | Diabetic endoneurial microenvironment | TNF-α, IL-1β, IL-6; miR-155, miR-146a-3p, miR-21-5p; PGE2, LTB4 | Sustained inflammatory responsiveness; positive feedback loop with Schwann cells; TRPV1 sensitization | The miR-155 → SOCS1 suppression → JAK-STAT amplification; delivery of lipid mediators to nociceptor terminals | Tertiary/reinforcing node – activated via endothelial barrier breakdown (DAMP exposure); feeds back onto Schwann cells (above) via miR-155/SOCS1/JAK-STAT, closing a self-amplifying loop |
| CD4+ T helper cells | Diabetic nerve infiltration | IFN-γ, TRAIL, FasL | Schwann cell apoptosis; impaired regenerative capacity | Induction of death receptor-mediated apoptosis in Schwann cells | Concurrent immune-effector node – acts in parallel with macrophage activation; compounds Schwann cell injury initiated upstream |
| CD8+ cytotoxic T cells | Diabetic nerve infiltration | Perforin, granzyme B | DRG neuron apoptosis | Perforin-mediated membrane poration and granzyme B-induced apoptosis | Concurrent immune-effector node – parallels CD4+ T cell action; extends peripheral cascade to DRG neuronal compartment |
| Regulatory T cells | Diabetes-associated dysfunction | Reduced TGF-β, IL-10 | Loss of anti-inflammatory exosomal signaling; removal of brake on neuroinflammation | Failure to suppress excessive immune activation | Permissive/disinhibiting node – loss of this regulatory checkpoint allows the macrophage/T-cell cascade above to proceed unchecked |
| Primary afferent central terminals | Hyperexcitable afferents (spinal dorsal horn) | Substance P, CGRP precursors; miRNAs targeting GABAergic interneuron function | Synaptic potentiation; reduced inhibitory tone; central sensitization | Transfer of pro-nociceptive cargo to second-order projection neurons and interneurons | Central propagation node – peripheral sensitization (Schwann cell/nociceptor arm above) is transmitted centrally via this route, initiating the spinal cascade below |
| Activated spinal microglia | Diabetic spinal cord | BDNF, IL-1β, miR-let-7c | Reduced KCC2 expression; loss of GABAergic inhibition; enhanced NMDA receptor-mediated transmission | BDNF-mediated downregulation of KCC2; impaired chloride extrusion | Central reinforcing node – activated by primary afferent input above; central counterpart to the peripheral macrophage feedback loop |
| Resting spinal microglia | Normoglycemia | Anti-inflammatory cargo; neuroprotective factors | Maintained synaptic homeostasis and inhibitory tone | Preservation of GABAergic function and KCC2 expression | Baseline/reference state – homeostatic phenotype contrasted against activated spinal microglia above |
| Reactive spinal astrocytes | Diabetic spinal cord | The miRNAs targeting GLT-1 and GLAST | Reduced glutamate clearance; glutamate spillover; sustained NMDA receptor activation | The miRNAs-mediated downregulation of astrocyte glutamate transporters | Central parallel node – co-occurs with microglial activation above; jointly sustains spinal central sensitization |
| Systemic circulation (to CNS) | Diabetes-compromised BBB | Peripherally derived pathological exosomes (e.g., from endothelial cells, immune cells) | Central sensitization; maladaptive CNS circuit remodeling | Delivery of pro-inflammatory and pro-nociceptive cargo to spinal and supraspinal centers | Terminal/integrative node – closes the peripheral-to-central loop by directly importing the vascular- and immune-conditioned exosome pool (rows 2, 6-9) into the CNS, independent of the synaptic relay route above |
| Biomarker category | Specific biomarker | Expression change in PDN | Mechanistic/clinical correlate | Diagnostic utility | Validation status and key specificity limitation |
| MiRNAs | MiR-21-5p | Upregulated | Targets PTEN (reduced) and PDCD4 (reduced) → enhanced PI3K-Akt survival signaling | Correlates positively with neuropathic pain scores, negatively with IENFD | Limited human PDN cohort data only; not PDN-specific – also upregulated in diabetic nephropathy, retinopathy, cardiomyopathy, and chemotherapy-induced neuropathy; no comparative cohort study has distinguished PDN from these conditions using this marker alone |
| MiR-146a-5p | Upregulated | Negative feedback regulator of TLR/IL-1R signaling (targets IRAK1, TRAF6); parallels increased IL-6 and TNF-α | Dynamic indicator of neuroinflammatory activity; correlates with disease duration and nerve conduction deficits | Supporting evidence derived from a DPN cohort using a ceRNA framework, not a pain-stratified PDN population; also elevated in diabetic nephropathy (a frequent PDN comorbidity), representing a critical confound for clinical diagnostic use without tissue-source enrichment | |
| Let-7a-5p, let-7b-5p | Downregulated | Derepresses HMGA2 → increased Nav1.7 transcription; derepresses IL-6Rα and STAT3 → increased IL-6 signaling | Molecular readout of peripheral nociceptor sensitization and neuroinflammation | Evidence is primarily preclinical (rodent DRG/spinal cord); no published human PDN cohort has confirmed circulating exosomal let-7 downregulation with clinical pain correlates; it is also dysregulated in diabetic retinopathy and hereditary neuropathies, limiting current specificity | |
| MiR-9-5p | Reduced | Impairs post-transcriptional suppression of NF-κB signaling in Schwann cells | Reflects Schwann cell pro-inflammatory phenotype | Mechanistic evidence only; no published PDN-specific human biomarker cohort data; lowest validation tier among listed miRNAs | |
| MiR-29 family | Downregulated | Promotes extracellular matrix accumulation and endoneurial fibrosis | Correlates with structural nerve remodeling | Mechanistic evidence only; endoneurial fibrosis correlation is inferred from general fibrosis biology rather than PDN-specific cohort data | |
| MiR-132-3p | Reduced | Derepresses RhoGAP32 → compromises axonal branching and synaptic plasticity | Indicates impaired axonal regeneration capacity | Dual role: Pathogenic exosomal cargo in PDN (Table 2) and therapeutic cargo in MSC-derived exosomes (Table 5); this context-dependency must be considered when interpreting circulating levels as a biomarker | |
| MiR-223-3p | Elevated | Derived from M1-polarized macrophages | Marker of endoneurial macrophage pro-inflammatory activation | Not PDN-specific; elevated in systemic inflammatory states; utility as a PDN biomarker depends on demonstrating neural-compartment specificity via L1CAM or MOG immunoaffinity enrichment (Table 4) | |
| Proteins | NfL | Elevated (exosomal fraction) | Axonal cytoskeletal damage; exosomal NfL correlates more strongly with neuropathy severity than total plasma NfL | Indicator of axonal degeneration; correlates with nerve conduction studies and IENFD | Best-validated protein biomarker in this table; however, NfL elevation is not PDN-specific (also elevated in AD, MS, ALS); the exosomal fraction advantage over total plasma NfL has not yet been validated in large independent PDN cohorts |
| HSP70 | Reduced | Neuroprotective chaperone normally enriched in healthy Schwann cell exosomes | Inversely correlates with neuropathic pain severity; reflects depletion of neuroprotective Schwann cell cargo | Reduction is consistent with hyperglycemia-induced Schwann cell dysfunction; relatively more PDN-contextual than miRNA markers since HSP70 enrichment is a Schwann cell-specific exosomal feature, though formal specificity studies across PDN comorbidities are lacking | |
| GAP-43 | Variable (higher in regenerative phenotype) | Expressed in regenerating axonal growth cones | Prognostic indicator of residual regenerative capacity; may guide timing of neuroprotective interventions | Prognostic rather than diagnostic marker; variable expression pattern limits use as a single threshold biomarker; most useful as part of a composite panel with NfL (degeneration) and HSP70 (Schwann cell support) to characterize individual patient disease trajectory | |
| MBP fragments, PMP22 | Elevated | Released from degenerating myelin sheaths; packaged into exosomes by activated macrophages | Correlates with slowing of motor and sensory nerve conduction velocities; marker of demyelinating neuropathy | Relevant specifically to large-fiber and demyelinating PDN subtypes; complementary to NfL (small-fiber/axonal marker); combined NfL + MBP/PMP22 panel could enable fiber-type-specific PDN subtyping, which has direct implications for therapeutic target selection |
| Tissue-specific signatures | Source | Method to enhance specificity | Key cargo detected | Clinical/anatomical window |
| Plasma/serum (neural-derived) | Immunoaffinity capture (L1CAM for neurons, MOG for Schwann cells) | Neuron- or Schwann cell-enriched exosomal cargo | Enables selective capture of neural exosomes from total circulating pool; improves diagnostic discrimination | Highest current clinical priority – accessible, scalable, and partially validated in adjacent conditions (TBI, AD); L1CAM enrichment has not yet been validated in PDN cohorts specifically, representing the most actionable near-term research gap |
| Skin blister fluid/dermal interstitial fluid | Direct sampling of affected area | TRPV1, substance P, pro-inflammatory miRNAs | Anatomically proximal to small fiber pathology; more powerful discrimination from pain-free diabetic controls than plasma | Anatomically ideal for PDN given distal lower extremity predilection; however, standardized blister induction and exosome isolation protocols are not yet established, limiting multi-site reproducibility |
| CSF | Lumbar puncture (research use) | BDNF, Iba1 fragments, miRNAs associated with NMDA receptor upregulation | Direct access to CNS compartment; reflects central sensitization state; distinguishes central vs peripheral pain mechanisms | Highest mechanistic specificity for central sensitization but invasiveness limits routine clinical use; most appropriate for research studies specifically designed to characterize spinal vs peripheral exosomal pathology in PDN |
| Urine | Non-invasive collection | The miR-21-5p (increased), let-7 family (reduced) | Practical advantages; partially mirror plasma signatures; requires validation for PDN vs diabetic nephropathy discrimination | Critical confound diabetic nephropathy independently alters urinary exosomal composition and co-exists in a significant proportion of PDN patients; urinary exosomal miRNA signatures cannot be attributed specifically to neuropathic pathology without concurrent nephropathy exclusion or renal-source depletion strategies |
A comprehensive and systematic literature search was conducted across four major electronic databases, including PubMed/MEDLINE, Scopus, Web of Science, and EMBASE, from database inception through March 2025, with no date restrictions applied to the search window. The search strategy was structured around three conceptual domains combined using Boolean operators (AND/OR): (1) Extracellular vesicles and exosomes, including the terms “exosome”, “extracellular vesicle”, “nanovesicle”, and “microvesicle”; (2) Diabetic neuropathy and neuropathic pain, including the terms “diabetic neuropathy”, “painful diabetic neuropathy”, “peripheral neuropathy”, “diabetic peripheral neuropathy”, and “neuropathic pain”; and (3) Mechanistic and therapeutic keywords, including “microRNA”, “miRNA”, “Schwann cell”, “neuroinflammation”, “mesenchymal stem cell”, “biomarker”, “drug delivery”, and “central sensitization”. To minimize publication bias and capture emerging evidence not yet indexed in peer-reviewed databases, gray literature sources were additionally searched, including ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, bioRxiv, and medRxiv. Manual screening of the reference lists of all included articles and relevant systematic reviews was performed to identify additional eligible studies not captured by the electronic database searches.
Studies investigating exosomes or extracellular vesicles in relation to diabetic neuropathy or neuropathic pain were eligible if they contributed evidence on at least one of the review’s three domains: (1) Pathogenesis; (2) Diagnostic biomarkers; and (3) Therapeutic applications. Evidence from experimental studies, clinical investigations, and relevant review articles was considered to provide a comprehensive overview of the field. Studies focusing exclusively on non-neurological diabetic complications or without specific relevance to exosome biology in neuropathy were excluded.
Retrieved records were screened through title/abstract and full-text review according to the eligibility criteria. Data were charted according to the review objectives, including exosomal source and cargo, pathogenic mechanisms, biomarker findings, therapeutic strategies, and major outcomes. Evidence was synthesized narratively to identify mechanistic relationships, translational advances, and remaining knowledge gaps. Because this was a scoping review, formal meta-analysis was not performed. To strengthen the interpretation of therapeutic evidence, a narrative risk-of-bias assessment was conducted for the principal preclinical studies and the single available human randomized controlled trial (RCT) using the Systematic Review Centre for Laboratory animal Experimentation and Cochrane Risk of Bias (RoB) 2 tools, respectively.
To strengthen the interpretation of therapeutic efficacy, a post hoc risk-of-bias assessment was performed for the key preclinical studies underpinning the efficacy ranges in Table 5 and the single identified human RCT[21]. Preclinical studies were assessed using the Systematic Review Centre for Laboratory animal Experimentation RoB tool, while the human RCT was evaluated using the Cochrane RoB 2.0 tool. Summary judgments (low, unclear, or high RoB) are presented in Table 6[12,13,23-25], with key methodological limitations highlighted alongside the corresponding efficacy data in Table 5. Consistent with the scoping nature of this review, this assessment provides a narrative appraisal rather than a formal systematic risk-of-bias synthesis and should be considered when interpreting the reported therapeutic effects.
| Category | Agent/approach | Mechanism of action/key cargo | Therapeutic outcomes/advantages | Evidence density/quality |
| Therapeutic rationale | Exosomes (general) | CD47 “don’t eat me” signal; natural barrier traversal; multi-molecular cargo delivery; surface engineerability | Bypasses limitations of single-agent drugs; non-genomic; immunologically well-tolerated; protects labile cargo | Conceptual/mechanistic rationale – not outcome-specific |
| Leading platform | MSC-derived exosomes | Cargo: BDNF, NGF, NT-3, GDNF, VEGF, HGF, HSP70/90, miR-146a, miR-223, let-7 family, miR-132-3p, miR-21-5p. Action: PI3K-Akt/MAPK-ERK activation; TLR4/NF-κB suppression; macrophage M2 polarization | Improves nerve conduction velocity (30%-60%), IENFD (35%-80%), and behavioral pain thresholds (40%-70%); reduces endoneurial TNF-α, IL-1β, iNOS; promotes structural regeneration | High – multi-study preclinical evidence base using consistent, composite functional/electrophysiological/behavioral outcome batteries |
| Preconditioning strategies | Hypoxic | Enriches HIF-1α products (VEGF, EPO, miR-210) | Enhanced endoneurial vascular restoration | Moderate – mechanistic enrichment data; outcome reported qualitatively |
| Inflammatory | Augments anti-inflammatory miR-146a and let-7b content. | Enhanced anti-inflammatory effect | Moderate – mechanistic enrichment data; outcome reported qualitatively | |
| Neurotrophic | Increases neurotrophic protein cargo | Enhanced DRG neuroprotection | Moderate – mechanistic enrichment data; outcome reported qualitatively | |
| Engineering for targeted delivery | Surface engineering | RVG peptide fusion (targets neuronal nAChRs); PEGylation | Increased DRG/peripheral nerve accumulation; extended circulation half-life (2-4 x) | Moderate-high – quantified pharmacokinetic data (half-life), but limited PDN-specific functional endpoint data |
| Cargo engineering | Electroporation (miRNA/siRNA); passive incubation (curcumin); parent cell genetic engineering (lactadherin C1C2 fusion) | Overcomes bioavailability limits (e.g., curcumin); enables scalable, enriched cargo production | Moderate – proof-of-concept delivery data; outcome reported qualitatively | |
| Mechanistically targeted cargo | let-7a mimic | Suppresses HMGA2-driven Nav1.7 transcription | Reduces ectopic discharge and mechanical allodynia without cardiac side effects | Moderate – single-mechanism preclinical study; qualitative behavioral outcome |
| Anti-TRPV1 siRNA | RVG-targeted knockdown of TRPV1 | Sustained reduction of thermal hyperalgesia from a single injection | Moderate – single-mechanism preclinical study; qualitative behavioral outcome | |
| MiR-146a-5p mimic | Reduces NF-κB activation and pro-inflammatory cytokines | Decreased endoneurial macrophage infiltration; improved nerve conduction and IENFD | Moderate – qualitative directional outcome; not consolidated into a quantified range | |
| Combined Cargo (let-7b-5p + miR-146a-5p) | Synergistic targeting of peripheral sensitization and neuroinflammation | Outperforms single-cargo preparations; demonstrates multiplex therapeutic advantage | Moderate – comparative (vs single-cargo) data; outcome reported qualitatively | |
| IL-4-stimulated macrophage exosomes | Enriched in IL-10, TGF-β, miR-124 | Suppresses microglial activation; restores KCC2 expression; reverses central sensitization | Moderate – proof-of-concept central-mechanism study; qualitative outcome | |
| Exosomal curcumin | Suppresses NF-κB activation | Superior anti-inflammatory efficacy vs free curcumin | Moderate – direct comparative study; qualitative outcome | |
| Alternative cell sources | Healthy Schwann cell-derived exosomes | Full physiological complement of neurotrophic cargo | Restores axonal mitochondrial function and IENFD more effectively than recombinant factors | Low-moderate – limited to comparison against single recombinant factors; no consolidated quantitative range or multi-domain (functional + electrophysiological + behavioral) outcome battery equivalent to MSC-derived exosome data |
| Plant-derived nanoparticles (ginger) | Enriched in phosphatidic acids and 6-gingerol | Attenuates NF-κB signaling and mechanical hyperalgesia; oral delivery possible; scalable and non-immunogenic | Low – limited to a single identified preclinical study; no IENFD, nerve conduction velocity, or quantified behavioral threshold data available; should be regarded as an early proof-of-concept signal rather than a validated efficacy estimate |
| Ref. | Study type | Model/population | Sequence generation | Baseline characteristics/allocation concealment | Random housing/blinding of personnel | Blinded outcome assessment | Incomplete outcome data | Selective outcome reporting | Overall RoB |
| Fan et al[13], 2020 | Preclinical (SYRCLE) | STZ-induced diabetic mouse; MSC-derived exosomes; IV administration | Unclear | Unclear | Unclear | High (behavioral endpoints unblinded) | Low | Unclear | High |
| Shan et al[12], 2022 | Preclinical (SYRCLE) | STZ-induced diabetic mouse; SIRT1-enriched bone marrow MSC exosomes | Unclear | Unclear | Unclear | High (unblinded outcome assessment reported) | Low | Unclear | High |
| Jia et al[23], 2018 | Preclinical (SYRCLE) | STZ-induced diabetic rat; high glucose-conditioned Schwann cell exosomes | Unclear | Unclear | Unclear | High (behavioral endpoints) | Low | Low | High |
| Lu et al[24], 2025 | Systematic review/meta-analysis (SYRCLE applied to included studies) | STZ-induced diabetic rodents; cell-derived exosomes | Unclear (majority of included studies) | Unclear (majority) | Unclear (majority) | High (majority of included studies) | Low | Low | High (majority of included studies) |
| Karkhaneh Yousefi et al[25], 2025 | Human RCT (Cochrane RoB 2.0) | Diabetic foot ulcer patients; Wharton’s jelly MSC-derived exosomes | Low | Low | Some concerns (personnel not blinded to treatment) | Some concerns (outcome assessors partially blinded) | Low | Low | Some concerns |
The principal methodological limitations identified across the preclinical studies included unclear allocation concealment, lack of blinded outcome assessment, small sample sizes (typically 6-10 animals per group), and inconsistent reporting of control conditions. Consequently, the reported efficacy ranges in Table 5 (30%-60% improvement in nerve conduction velocity, 35%-80% improvement in IENFD, and 40%-70% improvement in behavioral pain outcomes) should be regarded as estimates derived from a preclinical evidence base with a moderate RoB and interpreted cautiously pending confirmation in more rigorously designed studies. The literature identification and selection process is summarized in Figure 1.
Exosomes are formed through the endosomal pathway. Initially, early endosomes mature into late endosomes, whose limiting membrane undergoes inward budding to generate intraluminal vesicles (ILVs) within MVBs. ILV formation occurs through two major mechanisms. The first is the Endosomal Sorting Complex Required for Transport (ESCRT)-dependent pathway, in which the ESCRT-0, ESCRT-I, ESCRT-II, and ESCRT-III complexes sequentially recognize ubiquitinated cargo proteins and mediate membrane budding and scission. The second is an ESCRT-independent pathway involving ceramide, tetraspanins, and lipid raft microdomains.
Following ILV formation, MVBs fuse with the plasma membrane through mechanisms regulated by Ras-related protein, Rab27A, Rab27b, and Soluble N-ethylmaleimide-Sensitive Factor Attachment Protein Receptor proteins, resulting in the release of ILVs into the extracellular space as exosomes[26]. Exosomes generally range from 30 nm to 150 nm in diameter and are distinguished from other extracellular vesicles based on their biogenesis, size, and molecular composition. In contrast, microvesicles (100-1000 nm) originate through direct outward budding of the plasma membrane, whereas apoptotic bodies (> 1000 nm) are generated during programmed cell death. The International Society for Extracellular Vesicles (ISEV) recommends defining exosomes according to their biogenetic origin and surface marker expression rather than size alone, as outlined in the Minimal Information for Studies of Extracellular Vesicles 2018 guidelines[9].
Common exosomal surface markers used for identification and characterization include the tetraspanins CD9, CD63, and CD81, as well as ESCRT-associated proteins, tumor susceptibility gene (TSG101) and ALG-2-Interacting Protein X, and heat shock protein 70 (HSP70) and HSP90. In contrast, the absence of endoplasmic reticulum markers (calnexin), mitochondrial markers (cytochrome C), and nuclear markers (histones) is commonly used to confirm the purity of exosome preparations[9].
Exosomes carry a wide variety of biologically active molecules, including miRNAs, mRNAs, long non-coding RNAs, circular RNAs, and numerous proteins that have been extensively cataloged in databases such as ExoCarta and Vesiclepedia[27]. miRNAs are short non-coding RNAs, typically 18-22 nucleotides in length, that regulate gene expression by binding to the 3′ untranslated region of target mRNAs and suppressing protein translation. The loading of miRNAs into exosomes is a selective and regulated process. Proteins such as heterogeneous nuclear ribonucleoprotein A2/B1 recognize specific EXOmotif sequences within miRNAs, while neutral sphingomyelinase 2 contributes to ceramide-dependent sorting of cargo into exosomes[28].
The exosomal membrane is rich in sphingomyelin, cholesterol, ceramide, and phosphatidylserine, which provide structural stability and influence the distribution and uptake of exosomes by recipient cells. Importantly, exosomal cargo composition changes according to the physiological or pathological condition of the parent cell. Under pathological states such as hyperglycemia, oxidative stress, and inflammation, exosomes contain molecular cargo profiles that differ markedly from those produced under normal conditions. This disease-specific cargo alteration is considered a key factor underlying both the pathogenic role and biomarker potential of exosomes in PDN[29].
Exosomes interact with recipient cells through several mechanisms, including receptor-mediated endocytosis, macropinocytosis, and direct membrane fusion. Among these, direct membrane fusion is considered the most efficient method for delivering exosomal cargo into target cells and is more likely to occur in acidic environments such as inflamed or hypoxic tissues[30].
Once internalized, exosomal cargo can significantly influence recipient cell function. Transferred miRNAs regulate post-transcriptional gene expression, transferred kinases activate intracellular signaling pathways, and transferred epigenetic regulators modify the transcriptional activity of the recipient cell. Together, these processes can induce long-lasting phenotypic changes in recipient cells. Such sustained cellular reprogramming contributes to both the pathogenic and therapeutic roles of exosomes in PDN[30].
Chronic hyperglycemia triggers several interconnected biochemical pathways that contribute to the development and progression of diabetic neuropathy[7]. One major mechanism is activation of the polyol pathway, in which aldose reductase consumes nicotinamide adenine dinucleotide phosphate to convert glucose into sorbitol. This process reduces the availability of nicotinamide adenine dinucleotide phosphate required for glutathione regeneration, thereby weakening antioxidant defenses. In addition, intracellular sorbitol accumulation induces osmotic stress and further promotes mitochondrial superoxide production.
AGEs also accumulate under hyperglycemic conditions and cause structural modifications to myelin and cytoskeletal proteins. Furthermore, AGEs activate the receptor for advanced glycation end products expressed on Schwann cells, endothelial cells, and endoneurial macrophages, leading to persistent activation of the nuclear factor kappa B (NF-κB) signaling pathway and sustained neuroinflammation[31].
Mitochondrial dysfunction in dorsal root ganglion (DRG) neurons represents another critical pathological mechanism. This dysfunction is characterized by impaired adenosine triphosphate production, excessive generation of reactive oxygen species, disrupted calcium homeostasis, reduced peroxisome proliferator-activated receptor gamma coactivator 1-alpha-mediated mitochondrial biogenesis, and increased mitochondrial fragmentation. Collectively, these alterations impair axonal transport and reduce metabolic support to distal axons, ultimately contributing to neuronal degeneration and neuropathic dysfunction[32].
Progressive reduction in IENFD, commonly assessed using skin punch biopsies immunostained with the pan-axonal marker protein gene product (PGP9.5), is considered one of the most sensitive morphological biomarkers of small fiber neuropathy[33]. This reduction reflects the marked vulnerability of unmyelinated C-fibers and thinly myelinated Aδ-fibers to chronic metabolic and oxidative stress associated with diabetes. At the molecular level, voltage-gated sodium channel subtypes 1.7, 1.8, and 1.9 undergo hyperglycemia-induced functional alterations that lower the threshold for ectopic neuronal firing. In parallel, transient receptor potential (TRP) channels, TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) become upregulated and sensitized in response to neuroinflammation and oxidative stress. Together, these changes contribute to abnormal sensory signaling, leading to thermal hyperalgesia and mechanical allodynia that characterize PDN[34].
Endoneurial macrophage infiltration occurs early during the development of diabetic neuropathy and has been shown to correlate with neuropathic pain severity in both animal models and human nerve biopsy studies[35]. Activated macrophages produce pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, and matrix metalloproteinases. This inflammatory response is primarily driven by activation of the receptor for advanced glycation end products receptor and toll-like receptor 4 signaling pathways in response to damage-associated molecular patterns released from injured neurons.
At the same time, Schwann cells undergo pathological changes that further contribute to neuroinflammation. Under diabetic conditions, Schwann cells reduce the production of neurotrophic factors, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3, while increasing the release of inflammatory mediators such as monocyte chemoattractant protein-1 and TNF-α. These alterations enhance macrophage recruitment and directly sensitize nociceptive neurons through p38 mitogen-activated protein kinase (MAPK)-dependent signaling pathways[36].
Within the DRG, activation of satellite glial cells further amplifies peripheral neuroinflammation. Increased connexin 43-mediated gap junction communication and the release of pro-inflammatory cytokines create a local inflammatory microenvironment that lowers the excitability threshold of sensory neurons. This sustained peripheral sensitization is considered a major contributor to the spontaneous burning pain characteristic of PDN[37].
Persistent nociceptive input from damaged peripheral nerves induces spinal dorsal horn sensitization, including wind-up and long-term potentiation at C-fiber synapses within laminae I and II of the spinal cord. These processes are mediated primarily through activation of N-methyl-D-aspartate (NMDA) receptors and substance P/neurokinin-1 receptor signaling pathways[38]. Activated spinal microglia further contributes to central sensitization through the release of BDNF. BDNF activates Tropomyosin receptor kinase B receptors and suppresses the expression of the potassium-chloride cotransporter 2 (KCC2) in GABAergic interneurons, thereby reducing inhibitory neurotransmission and promoting central disinhibition. At the same time, activated astrocytes downregulate glutamate transporters-1 (GLT-1) and glutamate aspartate transporter (GLAST), resulting in extracellular glutamate accumulation and excessive activation of extrasynaptic NMDA receptors.
Alterations in descending pain modulatory pathways also contribute to the persistence of neuropathic pain in PDN. Descending noradrenergic inhibitory signaling becomes impaired, whereas facilitatory serotonergic signaling originating from the rostral ventromedial medulla is enhanced. Together, these central nervous system alterations create a pain-processing state that amplifies rather than suppresses nociceptive transmission, which may help explain why PDN is often resistant to therapies targeting only peripheral mechanisms[39]. It should be noted that the evidence supporting central sensitization mechanisms in below derives from a combination of directly demonstrated PDN model data and evidence extrapolated from broader neuropathic pain research. The wind-up, long-term potentiation, NMDA receptor activation, and microglial BDNF/KCC2 mechanisms described above have been directly demonstrated in streptozotocin-induced diabetic rodent models of PDN[38,39]. By contrast, the astrocytic GLT-1/GLAST downregulation and descending modulatory pathway alterations described here, while well-established in general neuropathic pain models, have been more limitedly demonstrated specifically in PDN models and should be regarded as mechanistically plausible extensions from non-PDN neuropathic pain literature rather than as PDN-specific confirmed findings. This distinction is summarized in Table 1 and is carried through to the exosomal propagation discussion below.
Chronic hyperglycemia promotes exosomal hypersecretion by activating neutral sphingomyelinase 2 and reactive oxygen species-dependent ESCRT signaling, resulting in increased exosome release from metabolically stressed neurons, Schwann cells, and glial cells[11]. This generalized increase in exosome secretion provides the foundation for the subsequent cell-specific cargo remodeling events described throughout this section. Similar findings have been reported in plasma from diabetic patients, high-glucose-treated Schwann cells, and sciatic nerve tissue from streptozotocin-induced diabetic rodents. Hyperglycemia also induces endothelial cells of the vasa nervorum to release exosomes enriched with pro-coagulant phosphatidylserine, tissue factor, and miRNAs that suppress endothelial nitric oxide synthase, thereby reducing nitric oxide bioavailability, impairing microvascular function, and promoting persistent endoneurial vasoconstriction[40].
These pathological endothelial exosomes further disrupt blood–nerve barrier integrity by targeting tight junction proteins, including claudins and occludin, and inducing pericyte apoptosis. The resulting increase in vascular permea
Importantly, these events are best viewed as an interconnected pathogenic cascade rather than isolated mechanisms. Endothelial dysfunction is likely to represent an early event that alters the endoneurial microenvironment through reduced perfusion and increased vascular permeability, thereby exposing Schwann cells and sensory neurons to sustained hypoxia, oxidative stress, and inflammatory mediators. These changes promote pathological remodeling of Schwann cell-derived exosomal cargo, enhance immune cell activation, and ultimately amplify neuroinflammation, axonal degeneration, and peripheral sensitization during PDN progression (Table 2)[23,41-43].
Under physiological conditions, Schwann cell-derived exosomes support neuronal survival and axonal maintenance by delivering neurotrophic factors such as NGF, BDNF, neurotrophin-3, and glial cell line-derived neurotrophic factor, together with metabolic substrates including pyruvate and lactate, as well as essential myelin-related components[42]. These exosomes play an important role in maintaining long-term peripheral nerve integrity and function.
However, under hyperglycemic conditions, the Schwann cell exosomal secretome undergoes pathological remodeling. The levels of neurotrophic factors are markedly reduced, whereas pro-apoptotic proteins, including cleaved caspase-3 and Bax, become elevated. In parallel, pro-inflammatory miRNAs such as miR-21-3p, miR-28-3p, and miR-34a ac
These pathological exosomes also enhance nociceptor sensitization. Reduced expression of let-7 family miRNAs derepresses high mobility group AT-hook 2 (HMGA2)-dependent Nav1.7 transcription, resulting in increased Nav1.7 and TRPV1 expression in recipient sensory neurons. Furthermore, exosomal delivery of ceramide and sphingosine-1-phosphate activates p38 MAPK and extracellular signal-regulated kinase signaling pathways, which further increase neuronal excitability through both transcriptional and post-translational mechanisms[23].
Notably, intraneural administration of hyperglycemia-conditioned Schwann cell exosomes into non-diabetic rodents has been shown to induce mechanical allodynia and thermal hyperalgesia. This finding demonstrates that pathological Schwann cell-derived exosomes can independently drive neuropathic pain even in the absence of systemic metabolic abnormalities.
Classically activated macrophage-derived exosomes, which represent the predominant inflammatory immune phenotype within diabetic peripheral nerves, are enriched with pro-inflammatory mediators including TNF-α, IL-1β, IL-6, miR-155, miR-146a-3p, and miR-21-5p. Transfer of miR-155 into Schwann cells suppresses suppressor of cytokine signaling 1 expression, leading to enhanced Janus kinase-signal transducer and activator of transcription pathway activation and establishing a positive neuroinflammatory feedback loop between macrophages and Schwann cells[43].
Macrophage-derived exosomes also contain inflammatory lipid mediators such as prostaglandin E2 and leukotriene B4, which directly sensitize TRPV1 channels at sensory nerve terminals and contribute to nociceptor hyperexcitability. In parallel, CD4+ T helper cell-derived exosomes carrying interferon-γ and Fas ligand promote Schwann cell apoptosis, while CD8+ cytotoxic T lymphocyte-derived exosomes containing perforin and granzyme B induce apoptosis of DRG neurons through perforin-mediated membrane damage[44].
Under normal conditions, regulatory T lymphocytes help suppress excessive inflammation through exosomal delivery of anti-inflammatory mediators such as transforming growth factor-β and IL-10. However, this protective anti-inflammatory signaling is impaired in diabetes, thereby removing an important regulatory mechanism that normally limits endoneurial immune activation and neuroinflammation.
Primary afferent neuron-derived exosomes within the spinal dorsal horn transport substance P, calcitonin gene-related peptide, and miRNAs that impair GABAergic interneuron function in second-order projection neurons. These exosomal signals contribute to synaptic potentiation and reduced inhibitory neurotransmission, thereby promoting central sensitization[45].
Activated spinal microglia further enhance neuropathic pain through the release of BDNF and IL-1β. These mediators suppress KCC2 expression, reduce GABAergic inhibitory signaling, and enhance NMDA receptor-mediated synaptic transmission, collectively contributing to central sensitization in diabetic neuropathic pain[46]. Reactive astrocytes also participate in this pathological process through exosome-mediated glial communication. Astrocyte-derived exosomes suppress the expression of GLT-1 and GLAST in neighboring astrocytes via miRNA-dependent mechanisms, leading to extracellular glutamate accumulation and excessive excitatory signaling.
To distinguish established findings from extrapolated mechanisms, this review differentiates evidence directly demon
Likewise, direct evidence that pathological peripheral exosomes cross the hyperglycemia-compromised BBB and contribute to spinal central sensitization in PDN is currently unavailable. This hypothesis is supported by studies showing exosome transport across a disrupted BBB in stroke, traumatic brain injury, and Alzheimer’s disease models[45], together with evidence that hyperglycemia increases BBB permeability in diabetic rodents[46]. Although these findings support the plausibility of peripheral-to-central exosomal signaling, direct confirmation in PDN will require studies tracking labeled exosomes in diabetic animal models.
A similar limitation applies to the intranasal delivery strategy discussed in below. Evidence that intranasally admini
Essentially, pathological exosomes generated in the peripheral nervous system may also cross the hyperglycemia-compromised BBB and enter the spinal cord. This extends the pathological exosomal signaling network into central pain-processing pathways and may help explain why central sensitization in PDN often persists even after peripheral glycemic control has improved[46]. Table 2 summarizes the role of exosomes in the pathogenesis of PDN. Collectively, these findings support a model in which exosomes function as dynamic mediators of cross-talk among vascular, glial, immune, and neuronal cells, linking peripheral metabolic injury with central pain processing throughout PDN progression.
Current diagnosis of PDN primarily relies on validated symptom questionnaires, clinical neurological examination, nerve conduction studies, and IENFD assessment from skin punch biopsies[33]. However, nerve conduction studies are relatively insensitive to early small fiber damage, while skin biopsy procedures are invasive and not routinely applicable in all clinical settings. Moreover, these diagnostic approaches provide limited mechanistic information regarding the underlying molecular and cellular processes driving PDN. Consequently, PDN is often diagnosed only after substantial and potentially irreversible axonal degeneration has already occurred.
Circulating exosomes have emerged as promising biomarker candidates with several advantages over conventional plasma biomarkers. Their lipid bilayer membrane protects internal cargo from degradation by circulating nucleases and proteases, thereby improving molecular stability. Additionally, exosomal cargo composition closely reflects the physiological and pathological state of their cells of origin, including neurons, Schwann cells, glial cells, and immune cells within the nervous system. Crucially, nervous system-derived exosomes can be detected in peripheral blood, allowing minimally invasive assessment of neuropathological changes. Furthermore, because exosomes carry multiple classes of biomolecules simultaneously, including proteins, lipids, and RNAs, they offer the potential for multiparametric biomarker panels with improved diagnostic and prognostic accuracy. This feature is particularly valuable in PDN, which is characterized by considerable pathophysiological heterogeneity[47].
It should be noted that the evidence supporting exosomal miRNA biomarkers in PDN is heterogeneous, comprising limited human cohort studies together with preclinical investigations in diabetic rodent models. Accordingly, the level of evidence for each biomarker is explicitly indicated below, and findings derived primarily from animal studies should be interpreted as mechanistic evidence rather than clinical validation.
Among the candidate biomarkers, miR-21-5p has shown the strongest clinical evidence. Limited human cohort studies have reported significantly elevated plasma exosomal miR-21-5p levels in PDN patients compared with diabetic individuals without neuropathy and healthy controls[15]. Exosomal miR-21-5p correlates positively with Neuropathic Pain Symptom Inventory scores and negatively with IENFD, suggesting an association with pain severity and small-fiber degeneration. Mechanistically, miR-21-5p targets phosphatase and tensin homolog and programmed cell death protein 4, although most evidence supporting these pathways derives from experimental studies rather than PDN-specific human investigations[15]. Furthermore, independent validation in large PDN cohorts remains limited.
A major limitation of miR-21-5p is its lack of disease specificity. Elevated circulating miR-21-5p has also been reported in diabetic nephropathy, retinopathy, cardiomyopathy, and several non-diabetic neurological disorders, including chemotherapy-induced peripheral neuropathy, HIV-associated neuropathy, and multiple sclerosis[15]. Moreover, no study has directly compared exosomal miR-21-5p across PDN, painless diabetic neuropathy, other diabetic complications, and non-diabetic neuropathic pain within the same cohort. Consequently, miR-21-5p should currently be regarded as a marker of generalized inflammatory and metabolic stress rather than a PDN-specific biomarker.
The miR-146a-5p has also emerged as a promising biomarker; however, the current human evidence is more limited. Available studies have reported elevated plasma miR-146a-5p in DPN cohorts, where it is associated with endoneurial macrophage infiltration and reduced nerve conduction velocity[16]. Nevertheless, these findings were obtained from DPN cohorts rather than pain-stratified PDN populations, and direct validation in patients with PDN remains unavailable.
Similar to miR-21-5p, miR-146a-5p lacks disease specificity, as it is also dysregulated in diabetic nephropathy and several inflammatory and neuropathic disorders. The frequent coexistence of diabetic nephropathy and PDN represents an important confounding factor because elevated circulating miR-146a-5p may reflect renal pathology rather than neuropathy alone, highlighting the need for neural-source enrichment strategies.
In contrast, evidence supporting the let-7 family (let-7a-5p and let-7b-5p) is derived predominantly from preclinical diabetic models[17]. Reduced let-7 expression has been associated with HMGA2-mediated Nav1.7 upregulation and enhanced IL-6/signal transducer and activator of transcription 3 signaling, providing a plausible mechanism for nociceptor sensitization and neuropathic pain. However, no published human PDN cohort has confirmed corresponding alterations in circulating exosomal let-7 expression. Moreover, reduced let-7 expression has also been reported in diabetic retinopathy, diabetic nephropathy, aging-associated neurodegeneration, and hereditary neuropathies[17], indicating that it is not specific to PDN.
Collectively, miR-21-5p, miR-146a-5p, and members of the let-7 family represent promising candidate exosomal biomarkers for PDN. However, their limited disease specificity is consistent with findings in other diabetic complications, including diabetic cardiomyopathy, where many of the same miRNAs regulate inflammatory, oxidative stress, and fibrotic pathways. These overlapping molecular signatures emphasize the need for prospective comparative validation across diabetic phenotypes before exosomal miRNA panels can be considered clinically useful PDN-specific biomarkers[48].
Additional dysregulated exosomal miRNAs implicated in PDN include miR-9-5p, which regulates NF-κB signaling in Schwann cells; miR-29 family members, associated with endoneurial fibrosis; miR-132-3p, involved in axonal branching through RAS p21 protein activator 1 suppression; and miR-223-3p, a marker of macrophage polarization. Together, these miRNAs form an interconnected regulatory network that may contribute to neuronal injury, glial dysfunction, neuroinflammation, and nociceptor sensitization in PDN.
Exosomal neurofilament light chain (NfL), a marker of axonal injury, is elevated in patients with PDN and demonstrates stronger correlations with neuropathy severity, nerve conduction abnormalities, and IENFD loss than do total plasma NfL levels[18]. This suggests that exosomal encapsulation may improve biomarker stability and increase the sensitivity of NfL detection in peripheral blood.
In contrast, exosomal HSP70, an important Schwann cell-associated neuroprotective chaperone protein, is reduced in PDN patients and inversely correlates with neuropathic pain severity. This reduction is consistent with hyperglycemia-induced impairment of Schwann cell neuroprotective function and depletion of beneficial exosomal cargo. Growth-associated protein 43, a marker of axonal regeneration and neural plasticity, has also been identified in circulating exosomes. Elevated exosomal growth-associated protein 43 levels may distinguish PDN patients with ongoing nerve regenerative activity from those with predominantly progressive neurodegeneration, thereby providing potential prognostic information relevant to therapeutic timing and disease progression.
In addition, myelin-related proteins such as myelin basic protein fragments and peripheral myelin protein 22 detected in macrophage-derived exosomes correlate with reduced nerve conduction velocity in demyelinating forms of PDN[19]. These exosomal protein biomarkers may therefore complement conventional electrophysiological assessments by providing molecular insight into large fiber and myelin pathology.
Plasma is currently the most practical and clinically accessible source for exosome analysis in PDN. However, because plasma contains exosomes released from multiple organs and tissues throughout the body, the neural-specific signal may be diluted. To improve specificity for nervous system-derived exosomes, immunoaffinity enrichment techniques using antibodies against neuronal markers such as L1 cell adhesion molecule or Schwann cell markers such as myelin oligodendrocyte glycoprotein have been developed. Similar enrichment approaches have already shown value in biomarker studies of traumatic brain injury and Alzheimer’s disease[20].
Skin blister fluid-derived exosomes may provide an alternative and potentially more sensitive source for assessing peripheral sensitization in PDN. These exosomes are enriched with pain-related molecules, including TRPV1, substance P, and pro-inflammatory miRNAs, allowing more direct evaluation of pathological processes occurring at the site of neuropathic pain generation.
Cerebrospinal fluid-derived exosomes more closely reflect central nervous system pathology and central sensitization mechanisms. They are enriched with molecules associated with neuroinflammation and central pain processing, including BDNF, Iba1 fragments, and NMDA receptor-related miRNAs. However, cerebrospinal fluid collection requires lumbar puncture, which limits its routine clinical applicability. Urine-derived exosomes represent another attractive non-invasive biomarker source and may partially reflect systemic pathological alterations associated with diabetes and neuropathy. Nevertheless, because diabetic nephropathy can also alter urinary exosomal composition, further studies are required to determine the specificity of urine-derived exosomal biomarkers for PDN[20].
Several methods are currently used to isolate exosomes, each with specific advantages and limitations. Differential ultracentrifugation is the most widely used technique; however, it often co-isolates contaminating materials such as protein aggregates and lipoproteins. Size exclusion chromatography generally provides higher exosome purity, although the final yield may be lower. Polymer-based precipitation kits are simple and convenient but frequently produce preparations contaminated with non-exosomal proteins and particles. In contrast, immunoaffinity capture techniques offer high specificity by selectively isolating exosomes expressing particular surface markers, although their accuracy depends heavily on the quality and validation of the antibodies used[49].
Beyond technical challenges in exosome isolation, the major barrier to clinical translation of exosomal miRNA biomarkers in PDN is the lack of comparative specificity data. As discussed below, candidate biomarkers including miR-21-5p, miR-146a-5p, and the let-7 family[15] are dysregulated in multiple diabetic complications and non-diabetic neuropathic disorders, limiting their disease specificity[16-20]. To date, no study has directly compared these biomarkers across PDN, painless diabetic neuropathy, diabetic nephropathy, and non-diabetic neuropathic pain within the same cohort. Consequently, their clinical utility remains unvalidated.
Future research should prioritize (1) Prospective comparative cohort studies including PDN and relevant diabetic and non-diabetic comparator groups; (2) Evaluation of neural-derived exosome enrichment strategies, such as L1 cell adhesion molecule-based or myelin oligodendrocyte glycoprotein-based immunoaffinity capture, to improve diagnostic specificity; and (3) Validation of multiparametric miRNA panels across diverse neuropathic conditions to determine whether their expression profiles are PDN-specific or reflect generalized peripheral nerve injury[20,49]. Until these studies are completed, exosomal miRNA panels should be regarded as promising, hypothesis-generating biomarkers rather than clinically validated diagnostic tools.
To ensure reliable exosome research, the ISEV recommends comprehensive characterization according to the Minimal Information for Studies of Extracellular Vesicles 2018 guidelines[9]. Minimum characterization standards include nanoparticle tracking analysis to determine particle size and concentration, transmission electron microscopy to confirm vesicle morphology, and detection of established exosomal surface markers such as CD63, CD9, CD81, and TSG101. At the same time, negative markers, including calnexin and albumin, should be assessed to confirm sample purity and exclude contamination from intracellular or plasma-derived proteins.
Accurate normalization of exosomal miRNA expression also remains a major methodological challenge. Commonly used housekeeping controls such as RNU6B and miR-16 may themselves become dysregulated under diabetic conditions, potentially introducing analytical bias. Therefore, validated external spike-in controls are recommended for more reliable normalization.
Before exosomal biomarkers can be translated into clinical practice for PDN, extensive clinical validation is required. This includes large prospective cohort studies with longitudinal follow-up, independent replication across different populations and geographic regions, and rigorous evaluation of assay performance characteristics such as sensitivity, specificity, receiver operating characteristic area under the curve, and inter-assay reproducibility under standardized clinical laboratory conditions[9]. Tables 3, 4 and 7 summarizes the major exosomal diagnostic biomarkers currently associated with PDN.
| Methodological considerations: Isolation method | Advantages | Limitations | Recommendation | Synthetic insight: PDN-specific consideration |
| Differential ultracentrifugation | Reference standard; widely used | Co-pellets aggregates, lipoproteins, other vesicle subtypes; operator-dependent | Requires standardized protocols (rotor type, g-force, time) | Most widely used in PDN biomarker studies to date, enabling cross-study comparison; however, co-pelleting of lipoproteins is a particular concern in diabetic patients, who frequently have dyslipidemia that elevates plasma lipoprotein levels |
| Size exclusion chromatography | Superior purity; maintains vesicle integrity | Reduced yield; requires specialized equipment | Suitable for protein biomarker studies | Preferred for NfL and protein biomarker studies in PDN given superior removal of lipoprotein contamination; recommended when exosomal protein rather than miRNA cargo is the primary analytical target |
| Polymer-based precipitation | Simple; scalable | Substantial non-vesicular contamination (protein aggregates, lipoproteins) | Caution advised for protein cargo analysis | Particularly unreliable in diabetic plasma due to elevated lipoprotein and acute-phase protein levels; not recommended for PDN biomarker discovery or validation studies |
| Immunoaffinity capture | High specificity for vesicle subpopulations | Requires validated antibodies; limited by incomplete knowledge of surface proteomes | Preferred for cell-type-specific exosome analysis | Critical enabling technology for PDN specificity: L1CAM capture for neuronal and MOG capture for Schwann cell-derived exosomes directly addresses the neural-signal dilution problem in plasma and is the recommended approach for PDN biomarker validation cohorts |
An ideal therapy for PDN would need to act on multiple disease mechanisms at the same time. It should reduce neuroinflammation, restore the supportive function of Schwann cells, decrease excessive pain signaling from peripheral nerves, promote axonal regeneration, and suppress central sensitization. However, no currently approved drug can achieve all of these effects simultaneously.
Current pharmacological management of PDN remains largely symptomatic, with pregabalin, duloxetine, and tapentadol providing pain relief but having limited effects on the underlying neurodegenerative process. Combination strategies are also being explored to improve efficacy while minimizing dose-related adverse effects. For example, a recent phase 1 study demonstrated that a fixed-dose combination of pregabalin and α-lipoic acid produced no clinically significant pharmacokinetic interaction and was well tolerated, supporting further evaluation of combination approaches in PDN[6]. Nevertheless, these strategies remain primarily symptomatic and do not directly address the underlying mechanisms of nerve degeneration. In contrast, exosome-based therapies have the potential to simultaneously modulate multiple pathogenic mechanisms, including neuroinflammation, oxidative stress, Schwann cell dysfunction, axonal degeneration, mitochondrial dysfunction, and neurovascular impairment, thereby offering a more comprehensive disease-modifying approach than current symptomatic treatments.
Exosomes have emerged as promising therapeutic candidates because of several natural advantages. Their surface protein CD47 interacts with signal regulatory protein alpha receptors on macrophages, helping them evade immune clearance and remain longer in circulation. Their lipid bilayer membrane protects fragile therapeutic cargo, such as miRNA mimics and small interfering RNAs (siRNAs), from degradation by serum nucleases. Exosomes can also naturally cross the blood-nerve and BBB, allowing delivery of therapeutic molecules into otherwise difficult-to-access neural tissues. In addition, exosomes carry multiple bioactive molecules simultaneously, enabling coordinated regulation of several pathological pathways. Their surface can also be engineered to improve targeting toward specific neural cell populations. Importantly, unlike viral vectors or recombinant protein therapies, MSC-derived exosomes are generally well-tolerated and do not integrate into the host genome[50].
MSC-derived exosomes can reproduce and, in some experimental studies, even surpass the neuroprotective, anti-inflammatory, and regenerative effects of their parent stem cells. Importantly, they avoid several safety concerns associated with live cell therapy, including ectopic engraftment, tumor formation, and pulmonary embolism[12]. MSC-derived exosomes are enriched with neurotrophic and angiogenic factors, including BDNF, NGF, glial cell line-derived neurotrophic factor, vascular endothelial growth factor (VEGF), and hepatocyte growth factor, together with regulatory miRNAs, which activate phosphatidylinositol 3-kinase-protein kinase B and MAPK/extracellular signal-regulated kinase signalling pathways to promote neuronal survival, axonal regeneration, and tissue repair[24,51-53]. MSC-derived exosomes may also carry molecular chaperones such as HSP70 and HSP90, which contribute to cytoprotection by attenuating endoplasmic reticulum stress and suppressing caspase-3-mediated apoptosis[27,51].
In addition, MSC-derived exosomes are enriched with anti-inflammatory miRNAs, including miR-146a, miR-223, and members of the let-7 family. These miRNAs suppress toll-like receptor 4/NF-κB inflammatory signaling in macrophages and Schwann cells, while promoting alternative macrophage polarization toward a tissue-repair and nerve-regeneration phenotype[51,54]. Specific exosomal miRNAs also contribute to peripheral nerve repair and regeneration. Exosomal miR-132-3p has been implicated in promoting neurite outgrowth and axonal regeneration through modulation of RAS p21 protein activator 1-mediated signalling, whereas exosomal miR-21-5p has been associated with enhanced neurite growth and Schwann cell-mediated repair under hyperglycaemia conditions. Collectively, these exosomal miRNAs contribute to neuronal survival, axonal regeneration, and functional recovery following peripheral nerve injury[14,50].
In streptozotocin-induced diabetic rodent models, intravenous administration of MSC-derived exosomes significantly improves both functional and structural features of diabetic neuropathy. Treatment restores sciatic motor nerve con
Exosomes derived from adipose tissue MSCs also promote vascular repair and angiogenesis through VEGF and pro-angiogenic miRNAs, including miR-132-3p, thereby improving the microvascular environment required for peripheral nerve regeneration[55-57]. Meanwhile, exosomes isolated from umbilical cord Wharton’s jelly MSCs, which are enriched with IGF-1, hepatocyte growth factor, and stanniocalcin-1, have shown superior therapeutic efficacy in several com
The therapeutic potential of MSC-derived exosomes can be further enhanced through parent-cell preconditioning before exosome collection. Different preconditioning strategies modify the biological cargo carried by exosomes and improve their therapeutic effects. For example, hypoxic preconditioning under low oxygen conditions (1%-5% O2) enriches exosomes with hypoxia-inducible factor-1α-regulated factors, including VEGF, erythropoietin, and miR-210, which enhance angiogenesis and improve endoneurial vascular restoration. Inflammatory preconditioning using cytokines such as TNF-α or IL-1β increases the levels of anti-inflammatory miRNAs, including miR-146a and let-7b, thereby strengthening the immunomodulatory effects of exosomes. Meanwhile, neurotrophic preconditioning with agents such as retinoic acid or sonic hedgehog agonists enhances the loading of neurotrophic proteins into exosomes, resulting in greater DRG neuroprotection and regenerative capacity compared with exosomes derived from unmodified MSC cultures[59].
Native MSC-derived exosomes exhibit limited neural targeting following systemic administration, as they are rapidly sequestered by hepatic Kupffer cells and splenic macrophages, with most particles cleared from circulation within approximately 30 minutes in rodent pharmacokinetic studies. To overcome these limitations, several engineering strategies have been developed to enhance exosomal stability, targeting specificity, and therapeutic delivery[60].
One major approach involves surface engineering, in which targeting ligands are displayed on the exosomal membr
Additional modifications aim to prolong exosomal circulation time. Polyethylene glycol (PEG) conjugation, which involves coating exosomes with PEG, reduces recognition and clearance by the mononuclear phagocyte system, thereby extending circulation by approximately two-fold to four-fold. Importantly, combining PEG conjugation with neural-targeting ligands produces “stealth-targeted” exosomes that exhibit synergistically enhanced accumulation within neural tissues and improved therapeutic potential[60].
Cargo engineering strategies have been developed to enhance the therapeutic potential of exosomes by improving the loading and delivery of bioactive molecules. Electroporation is commonly used to load miRNA mimics and siRNA into exosomes, while passive incubation is suitable for incorporating lipophilic compounds such as curcumin. Notably, exosome-encapsulated curcumin demonstrates greater accumulation in nerve tissue and stronger anti-inflammatory effects compared with free curcumin formulations, largely because exosomal delivery helps overcome the poor oral bioavailability and limited stability of curcumin[60].
Another advanced strategy involves genetic engineering of the parent MSCs to overexpress therapeutic miRNAs or neurotrophic proteins. These therapeutic cargoes are often fused to lactadherin C1C2 endosomal sorting sequences, which facilitate their efficient incorporation into exosomes during natural exosome biogenesis. This approach enables scalable production of cargo-enriched exosomes while avoiding the physical disruption and structural damage that may occur with post-isolation loading techniques[60].
At the peripheral nociceptor level, engineered exosomes have demonstrated significant therapeutic potential in diabetic neuropathy by targeting multiple pain-related mechanisms simultaneously. Delivery of exosomal let-7a mimics suppresses HMGA2-mediated Nav1.7 transcription in DRG neurons, thereby reducing ectopic neuronal firing and mechanical allodynia in streptozotocin-induced diabetic mice. Prominently, this targeted approach avoids the cardiac conduction adverse effects commonly associated with systemic sodium channel antagonists. Similarly, RVG-targeted exosomal delivery of siRNA against TRPV1 produces sustained TRPV1 knockdown and prolonged reduction of thermal hyperalgesia lasting several weeks after a single intraneural injection, substantially exceeding the duration of action achieved with conventional small-molecule TRPV1 antagonists.
Exosomal miRNA therapies also exhibit potent anti-inflammatory actions. Delivery of miR-146a-5p mimics reduces endoneurial macrophage infiltration, suppresses NF-κB activation, and decreases pro-inflammatory cytokine production, leading to improvements in nerve conduction velocity and IENFD. Furthermore, combined exosomal cargo preparations containing both let-7b-5p and miR-146a-5p mimics target peripheral sensitization and neuroinflammation simultaneously. These dual-cargo exosomes consistently outperform single-cargo formulations across multiple experimental endpoints, highlighting the unique multiplex therapeutic capability of exosomal platforms that cannot be readily achieved using conventional single-molecule pharmacological therapies.
At the spinal cord level, intrathecal administration of exosomes derived from IL-4-stimulated macrophages, enriched with IL-10, transforming growth factor-β, and miR-124, suppresses microglial activation, restores KCC2 expression, and reverses mechanical allodynia in diabetic rodents. These findings provide important proof of concept that exosomal therapies can also target central sensitization mechanisms in PDN. In addition, exosome-mediated curcumin delivery demonstrates significantly greater anti-inflammatory efficacy in diabetic peripheral nerves compared with free curcumin administered at equivalent doses, primarily through the suppression of NF-κB signaling and macrophage-derived pro-inflammatory cytokine production[14,43].
It should be acknowledged at the outset that the depth of quantitative evidence available for alternative exosome sources discussed in this section is substantially lower than that available for MSC-derived exosomes (Table 5), and this disparity reflects an underlying difference in the maturity of the respective evidence bases rather than equivalent therapeutic promise. Accordingly, the following discussion is explicitly stratified by evidence density, and quantitative outcome data are reported wherever available rather than presented in qualitative terms alone.
Healthy Schwann cell-derived exosomes contain a natural and physiologically balanced combination of neurotrophic factors, miRNAs, and bioactive molecules that support nerve repair and regeneration. In diabetic rodent models, these exosomes restore axonal mitochondrial function and IENFD more effectively than supplementation with individual recombinant neurotrophic factors alone. However, the supporting literature for this comparison consists of a small number of mechanistic studies using direct head-to-head comparisons against single recombinant neurotrophic factors rather than against the broader composite functional, electrophysiological, and behavioral endpoint battery used to characterize MSC-derived exosomes in Table 5; consequently, comparable consolidated percentage-improvement ranges for nerve conduction velocity, IENFD, or pain-related behavior cannot currently be derived for Schwann cell-derived exosomes with the same confidence, and this evidence should be regarded as moderate-density, mechanistically informa
In addition to mammalian exosomes, plant-derived exosome-like nanoparticles have also emerged as promising therapeutic platforms for PDN. Ginger-derived nanoparticles, which are enriched with anti-inflammatory phosphatidic acids and bioactive phytochemicals such as 6-gingerol, have been shown to suppress NF-κB signaling and improve mechanical hyperalgesia in streptozotocin-induced diabetic mice following oral administration[35,36]. This evidence base is presently limited to a single identified preclinical study and consequently represents the lowest-density evidence tier discussed in this review; no IENFD, nerve conduction velocity, or multi-domain behavioral outcome data equivalent to those summarized in Table 5 for MSC-derived exosomes are currently available for ginger-derived or other plant-derived nanoparticles. The qualitative description of mechanical hyperalgesia improvement in the cited study should therefore not be interpreted as indicating therapeutic efficacy comparable in magnitude or robustness to the quantified MSC-exosome outcomes, but rather as an early proof-of-concept signal warranting further dose-ranging and multi-endpoint preclinical evaluation before any comparative efficacy claim can be supported. These plant-derived nanoparticles offer several practical advantages, including high scalability, low immunogenicity, and the convenience of oral delivery, making them particularly attractive for long-term management of chronic PDN. Table 5 summarizes the therapeutic applications of exosomes and exosome-like nanoparticles in PDN.
The route of exosome administration plays a critical role in determining therapeutic distribution and efficacy in PDN. Intravenous administration allows systemic distribution of exosomes; however, a large proportion is rapidly cleared by the mononuclear phagocyte system, particularly by hepatic and splenic macrophages. Consequently, this delivery route often requires surface engineering modifications or repeated dosing to maintain sufficient therapeutic concentrations.
In contrast, ultrasound-guided perineural injections deliver exosomes directly near the affected nerve, resulting in high local endoneurial concentrations and greater therapeutic efficacy compared with intravenous administration at equiva
Intranasal administration represents another promising non-invasive strategy. This route exploits the olfactory and trigeminal nerve pathways to transport exosomes into the central nervous system, including the lumbosacral spinal cord, within approximately 60 minutes. As a result, intranasal delivery may provide an effective method for targeting spinal cord-mediated central sensitization without requiring invasive intrathecal injections.
Additionally, transdermal microneedle-array delivery enables localized targeting of intraepidermal nerve fibers through minimally invasive skin penetration. Preliminary studies in diabetic rodents have demonstrated that this method reduces footpad TRPV1 expression and substance P levels, supporting its potential as a localized therapeutic strategy for PDN[58].
Clinical translation of exosome-based therapy requires production at a much larger scale than that used in laboratory research, while maintaining strict, good manufacturing practice (GMP) standards and consistent batch-to-batch quality[61]. Among the currently available manufacturing approaches, hollow fiber bioreactors are considered among the most promising scalable platforms because they can produce approximately five-fold to ten-fold higher exosome yields per cell than conventional flask-based culture systems, while still preserving exosomal cargo consistency[62].
Despite their therapeutic promise, the clinical translation of exosome-based therapies remains constrained by manufacturing cost, product consistency, and regulatory readiness. Current GMP-grade MSC-derived exosome production is estimated to cost approximately USD 5000-50000 per patient dose, based primarily on oncology and wound-healing programs, and remains substantially more expensive than existing PDN therapies. Because PDN-specific dosing regimens have not yet been established, the eventual cost-effectiveness of this approach remains uncertain and will depend on scalable manufacturing processes[60].
Existing GMP manufacturing platforms, including Wharton’s jelly MSC-derived exosomes and hollow-fiber bioreactor systems, have demonstrated acceptable batch consistency for particle size, exosomal markers (CD63, CD9, CD81), and sterility. However, reproducibility of therapeutic cargo, particularly miRNAs and neurotrophic proteins, remains insufficiently characterized, and large-scale batch consistency suitable for phase II/III trials has yet to be demonstrated[60].
As of the March 2025 literature search, neither the Food and Drug Administration (FDA) nor the European Medicines Agency (EMA) had issued dedicated guidance for exosome-based therapeutics. Consequently, clinical development currently relies on case-by-case regulatory review, increasing development complexity and cost. Early engagement with regulatory programs such as the FDA Emerging Technology Program and EMA Innovation Task Force is therefore recommended to facilitate manufacturing development and future clinical translation[62,63].
To ensure safety, quality, and therapeutic reliability, clinical-grade exosomes must undergo comprehensive release testing before use. These evaluations include assessment of exosome identity using nanoparticle tracking analysis, bead-based multiplex flow cytometry for surface marker profiling, and electron microscopy for structural confirmation. Purity testing is also essential and typically involves endotoxin detection using the Limulus Amebocyte Lysate assay, sterility testing, and mycoplasma screening.
In addition, potency testing is required to confirm biological activity. Common assays include evaluation of neurite outgrowth induction in DRG neurons, suppression of inflammatory cytokine production in stimulated macrophages, and validated reverse transcription quantitative polymerase chain reaction analysis of therapeutic miRNA cargo. Stability testing under defined storage conditions, such as -80 °C or liquid nitrogen preservation, is also necessary to ensure long-term product integrity[49]. Published stability data from GMP exosome programs indicate acceptable retention of particle concentration and surface marker expression after storage at -80 °C for up to 12 months, but equivalent long-term stability data for therapeutic miRNA cargo and neurotrophic protein content under GMP storage conditions are not yet consistently reported and represent a further gap in the translational evidence base. Despite rapid progress in the field, internationally standardized release criteria and regulatory specifications for exosome-based therapeutics remain lacking, highlighting an urgent need for global harmonization[61].
In the United States, the FDA regulates exosome-based therapies as biological products under Section 351 of the Public Health Service Act, requiring an Investigational New Drug application supported by comprehensive preclinical data, including physicochemical characterization, biodistribution, pharmacokinetics, toxicology, and safety assessments[63]. Similarly, the EMA regulates these products within the Advanced Therapy Medicinal Products framework, with scientific evaluation by the Committee for Advanced Therapies before clinical development and marketing authorization[64].
However, the principal regulatory challenge extends beyond conventional Investigational New Drug or Advanced Therapy Medicinal Products requirements. Unlike recombinant biologics or small-molecule drugs, exosomes are highly heterogeneous vesicle populations whose therapeutic activity arises from the combined effects of multiple proteins, lipids, and nucleic acids rather than a single defined active ingredient. Consequently, establishing robust potency assays that reliably predict biological activity remains one of the major barriers to regulatory approval. Current quality-control testing can confirm particle size, concentration, sterility, and expression of exosomal markers such as CD9, CD63, and CD81, but these measurements do not necessarily reflect therapeutic potency or cargo functionality[63,64].
Standardized potency assays, validated cargo characterization, and internationally harmonized quality standards are therefore considered essential for successful clinical translation. Development of such standards through collaboration among regulatory agencies, the United States Pharmacopeia, European Pharmacopeia, and the ISEV will be critical to support future regulatory approval of exosome-based therapies[62,63].
As of the March 2025 search cutoff, more than 90 registered clinical trials are investigating exosome-based therapies for various oncological, neurological, and inflammatory diseases[64]. Among these, studies involving MSC-derived exosomes for diabetic wound healing have provided important preliminary evidence supporting the safety of exosome administration in diabetic patients. Notably, an RCT using Wharton’s jelly MSC-derived exosomes for diabetic foot ulcers reported no serious adverse events and demonstrated significantly faster wound healing compared with standard treatment alone[25].
It must be explicitly acknowledged, however, that diabetic foot ulcer and PDN are mechanistically and clinically distinct conditions. Diabetic foot ulcer involves dermal and soft tissue repair in a hyperglycemic wound environment, whereas PDN involves neuroprotection, axonal regeneration, peripheral nociceptor desensitization, and suppression of spinal central sensitization within the nervous system. The therapeutic cargo requirements, target tissues, pharmacokinetic demands, and outcome measures relevant to PDN are therefore fundamentally different from those evaluated in the foot ulcer RCT, and the safety and efficacy signals from that trial cannot be directly extrapolated to a PDN indi
The reasons why no PDN-specific exosome trial has been initiated despite approximately two decades of exosome research merit explicit examination, as understanding these barriers is essential for designing a credible translational pathway. Several interconnected factors are identifiable. First, the absence of GMP-compliant, PDN-specific exosome manufacturing programs reflects the fact that the field has prioritized oncological and wound-healing indications, where regulatory precedents and commercial incentives are more developed; PDN has not yet attracted equivalent industry investment, partly because the approved pharmacotherapy landscape (pregabalin, duloxetine) creates a commercially lower-urgency environment despite its acknowledged therapeutic inadequacy. Second, the absence of validated PDN-specific potency assays and pharmacodynamic biomarkers mean that no developer can currently demonstrate to a regulatory agency that its exosome product is engaging the intended biological target in a human PDN patient, a prerequisite for phase II dose selection and go/no-go decisions. Third, the route-of-administration uncertainty described in below, specifically whether intravenous, perineural, intranasal, or transdermal delivery is required to achieve therapeutic endoneurial concentrations sufficient to affect IENFD, has not been resolved in large animal models, making it premature to commit to a clinical delivery strategy. Fourth, the composite endpoint challenge identified in below (IENFD as a disease-modification endpoint requiring 12-18 months of follow-up in human trials) makes PDN a resource-intensive indication relative to oncology indications where surrogate endpoints are more rapidly assessable. Together, these barriers explain the current clinical gap and collectively define the minimum preclinical and manufacturing research agenda that must be completed before a first-in-human PDN trial can be responsibly initiated.
Despite these encouraging developments, no registered clinical trial has specifically evaluated exosome-based therapy for PDN, representing a major gap in current translational research[58]. The development of exosomal therapies for PDN also requires careful consideration of disease-specific safety concerns. Patients with PDN frequently present with comorbid conditions such as cardiovascular autonomic neuropathy and diabetic nephropathy, which may alter drug pharmacokinetics, and diabetes-associated immune dysfunction. Consequently, future clinical trials should incorporate tailored safety monitoring strategies, including cautious dose-escalation protocols, independent Data Safety and Monitoring Board oversight, and predefined stopping criteria to ensure patient safety throughout the study period.
Future phase I/II clinical trials investigating exosome-based therapies for PDN should recruit patients with confirmed moderate PDN using validated clinical assessment tools, including the Neuropathic Pain Symptom Inventory, Brief Pain Inventory, and Douleur Neuropathique 4 questionnaire, together with objective evidence of neuropathy based on nerve conduction studies, IENFD, or quantitative sensory testing[33].
Composite primary endpoints combining changes in the 11-point numeric pain rating scale with IENFD may enable simultaneous assessment of symptomatic improvement and structural nerve regeneration, thereby addressing the limitation of previous PDN trials that focused predominantly on pain relief[33]. Recent clinical advances demonstrate that structural nerve regeneration is an achievable therapeutic objective in DPN. For example, a phase 2a randomized trial showed that topical pirenzepine significantly increased IENFD, providing proof of concept that disease-modifying therapies targeting nerve regeneration can produce measurable structural improvement, although larger phase 2b and phase 3 studies remain necessary[6]. Compared with such single-target approaches, exosome-based therapies may offer broader therapeutic potential by simultaneously modulating neuroinflammation, Schwann cell dysfunction, axonal degeneration, mitochondrial dysfunction, and neurovascular impairment. Whether these mechanistic advantages translate into superior clinical outcomes remains to be established through well-designed human clinical trials. However, meaningful improvement in IENFD will depend on achieving sufficient exosome exposure within peripheral nerves. As discussed in the previous part, intravenously administered exosomes undergo substantial hepatic and splenic clearance, and the optimal dose, dosing frequency, and delivery route required to achieve therapeutic concentrations in peripheral nerve tissue remain unknown[60]. Early-phase clinical trials should therefore incorporate pharmacokinetic and biodistribution assessments to determine whether adequate target engagement is achieved before interpreting structural endpoints such as IENFD.
Secondary endpoints should include nerve conduction velocity, quantitative sensory testing, quality-of-life measures, and longitudinal assessment of circulating exosomal biomarkers to establish pharmacodynamic and mechanistic relationships[25]. Biomarker-guided patient stratification may further support precision medicine by identifying neuroinflammatory, neurodegenerative, or nociceptor-sensitization phenotypes, although this approach requires prospective validation[11]. Future trials should also include both male and female participants with adequate statistical power, given recognized sex-related differences in pain processing, microglial activation, and Schwann cell regenerative responses[63].
The evidence[11,14] reviewed demonstrates that exosome-mediated intercellular communication is a central mechanism in PDN pathogenesis, linking metabolic injury, neuroinflammation, axonal degeneration, and central sensitization through interactions among neurons, Schwann cells, immune cells, and vascular cells[23,43-46]. In parallel, MSC-derived, engineered, and miRNA-loaded exosomes show substantial therapeutic efficacy across behavioral, molecular, and structural outcomes in preclinical diabetic models, supporting their potential as multi-target disease-modifying therapies[52-54,65].
However, current evidence remains predominantly preclinical. Therapeutic efficacy has been demonstrated only in diabetic animal models, while human data are limited to MSC-derived exosome studies in diabetic foot ulcers rather than PDN[25]. Likewise, circulating exosomal miRNAs (miR-21-5p, miR-146a-5p, and the let-7 family) and protein biomarkers (NfL and HSP70) remain promising candidate biomarkers, but their diagnostic specificity requires validation in six prospective comparative studies[15-20]. Proposed peripheral-to-central exosomal signaling also remains mechanistically plausible but incompletely demonstrated in PDN[45,46].
Future clinical translation will require optimization of dosing and delivery strategies, development of PDN-specific potency assays, validation of biomarker panels, establishment of GMP-compliant manufacturing, early regulatory engagement, and first-in-human clinical trials incorporating exploratory biomarkers such as IENFD and circulating exosomal signatures[25,60].
Overall, exosome biology provides a compelling platform for developing disease-modifying strategies for PDN. Nevertheless, substantial manufacturing, regulatory, pharmacokinetic, and clinical validation challenges remain before exosome-based therapies can be translated into routine clinical practice.
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