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

Table 4 Summary of tissue-specific signatures

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

PDN: Painful diabetic neuropathy; miRNAs: MicroRNAs; L1CAM: L1 cell adhesion molecule; MOG: Myelin oligodendrocyte glycoprotein; TBI: Traumatic brain injury; TRPV1: Transient receptor potential vanilloid 1; CSF: Cerebrospinal fluid; BDNF: Brain-derived neurotrophic factor; NMDA: N-methyl-D-aspartate; CNS: Central nervous system; AD: Alzheimer’s disease.