Exosomes as emerging mediators and therapeutic vehicles in painful diabetic neuropathy: From pathophysiology to clinical translation

Table 2 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 Painful diabetic neuropathy progression

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

ESCRT: Endosomal Sorting Complex Required for Transport; LDL: Low-density lipoprotein; eNOS: Endothelial nitric oxide synthase; NO: Nitric oxide; NGF: Nerve growth factor; BDNF: Brain-derived neurotrophic factor; NT-3: Neurotrophin-3; GDNF: Glial cell line-derived neurotrophic factor; HSP70: Heat shock protein 70; Bax: Bcl-2-associated X protein; HMGA2: High mobility group AT-hook 2; TRPV1: Transient receptor potential vanilloid 1; p38 MAPK: P38 mitogen-activated protein kinase; ERK: Extracellular signal-regulated kinase; TNF-α: Tumor necrosis factor-alpha; IL: Interleukin; PGE2: Prostaglandin E2; LTB4: Leukotriene B4; SOCS1: Suppressor of cytokine signaling 1; JAK-STAT: Janus kinase-signal transducer and activator of transcription; IFN-γ: Interferon-gamma; TRAIL: Tumor necrosis factor-related apoptosis-inducing ligand; DRG: Dorsal root ganglion; TGF-β: Transforming growth factor-β; CGRP: Calcitonin gene-related peptide; GABA: Gamma-aminobutyric acid; KCC2: Potassium-chloride cotransporter 2; NMDA: N-methyl-D-aspartate; GLT-1: Glutamate transporters-1; GLAST: Glutamate aspartate transporter; CNS: Central nervous system; DAMP: Damage-associated molecular pattern; miRNAs: MicroRNAs; nSMase2: Neutral sphingomyelinase 2; FasL: Fas ligand; M1: Classically activated macrophage; BBB: Blood-brain barrier.