Therapeutic applications of mesenchymal stem cell-derived extracellular vesicles in pain management: A narrative review of emerging evidence and future directions

Table 1 Recent preclinical evidence (qualitative data) for pain management using mesenchymal stem cell-derived extracellular vesicles

MSC source	In vitro experimental model	In vivo experimental model	Pain type	Key findings (qualitative analysis)	Mechanistic outcomes	Ref.
Mouse bone marrow MSCs	-	Partial sciatic nerve ligation in male C57BL/6	Neuropathic pain	MSCs produced long-lasting anti-nociception	Decreased IL-1β, TNF-α, and IL-6	[103]
				Reduced thermal hyperalgesia and mechanical allodynia	Increased IL-10
					Secretome factors (VEGF, HGF chemerin, angiopoietin-1) mediating neuroprotection and immune modulation
Mouse bone marrow MSCs	-	Diabetic db/db mouse model	Neuropathic pain	Increased thermal and mechanical sensitivity	Suppressed inflammatory cytokines	[107]
				Increased motor and sensory nerve conduction velocities	Macrophage polarization from M1 to M2
				Increased intraepidermal nerve fiber density, myelin thickness, and axonemal diameter	Exosomal miRNAs targeted the TLR4/NF-κB pathway, reducing inflammation
				Reduced neuroinflammation and macrophage infiltration in the sciatic nerve
Rat bone marrow MSCs	IL-1β-treated rat chondrocytes	Rat OA model induced by sodium iodoacetate	Osteoarthritis pain	BMSC exosomes prolonged paw-withdrawal latency in OA rats	Reduced nociceptor mediator CGRP, decreasing neuronal sensitization	[108]
				Reduced CGRP and iNOS protein levels in DRG tissue	Reduced iNOS and inflammation
				Indicated relief of both inflammatory and neuropathic components of pain	Modulated anti-inflammatory cytokines
				Protected cartilage, indirectly reducing pain drivers
hPMSCs	-	Nerve injury mouse model	Neuropathic pain	An intrathecal dose reversed mechanical allodynia	miR-26a-5p targeted Wnt5a and downstream Wnt5a/Ryk/CaMKII/NFAT signaling	[109]
				Produced long-lasting analgesia	Reduced neuroinflammation
				Labeled EVs localized to microglia and neurons in the dorsal horn	Decreased TNF-α, IL-1β, and IL-6
				miR-26a-5p-rich hPMSC-EVs significantly reduced neuropathic pain and neuroinflammation	Inhibited microglial activation
					Mediated anti-neuroinflammatory and analgesic effects
hUC-MSCs	LPS and ATP-stimulated BV2 microglia	CFA-induced inflammatory pain in C57BL/6 mice	Inflammatory pain	hUC-MSC exosomes reduced mechanical allodynia and thermal hyperalgesia	Attenuated inflammation-driven pain via the miR-146a-5p/TRAF6/autophagy-pyroptosis axis	[110]
				Reduced microglial activation and neuroinflammation
				Increased autophagy
hUC-MSCs	LPS-stimulated BV2 microglia	CCI rat model	Neuropathic pain	MSC-EVs reduced pain	EV miR-99b-3p inhibited the PI3K/AKT/mTOR pathway	[104]
				Reduced microglial activation and inflammation	Increased autophagy
				Restored autophagy via miR-99b-3p delivery	Reduced proinflammatory cytokines
Human bone marrow MSCs	-	High-fat diet plus groove surgery in rats	Osteoarthritis pain	MSC-EVs reduced structural joint degeneration and inflammation more than MSCs	Lower immunogenicity; reduced inflammation and cartilage catabolism	[111]
				EV-treated rats showed less cartilage damage, osteophytosis, synovitis, and pain-associated behavior	Synovitis drove pain and osteophyte formation
Human bone marrow MSCs	NGF-sensitized DRG neurons	DMM-induced OA in mice	Osteoarthritis pain	Prevented pain-related behaviors	Direct action of MSC-EVs on sensory neurons normalized hyperexcitability	[82]
				MSC-EVs prevented NGF-induced hyperexcitability in cultured DRG neurons in vitro	Reduced release of proinflammatory mediators in the joint environment
hUC-MSCs	DRG primary culture from SD rats	Paclitaxel-induced peripheral neuropathy in C57BL/6J mice	Chemotherapy-induced peripheral neuropathy	Cannabidiol-loaded hUC-MSC-EVs reduced paclitaxel-induced mechanical allodynia and thermal hyperalgesia	AMPK pathway activation	[48]
				Normalized mitochondrial function in DRG and spinal cord of treated mice	Increased mitochondrial function and bioenergetics
					Modulated oxidative stress and inflammation by upregulating Nrf2 and downregulating NF-кB
					Provided additional regenerative support

MSCs: Mesenchymal stem cells; IL: Interleukin; TNF: Tumor necrosis factor; VEGF: Vascular endothelial growth factor; HGF: Hepatocyte growth factor; miRNAs: MicroRNAs; TLR4: Toll-like receptor 4; NF-кB: Nuclear factor kappa B; OA: Osteoarthritis; BMSC: Bone mesenchymal stem cell; CGRP: Calcitonin gene-related peptide; iNOS: Inducible nitric oxide synthase; Wnt5a: Wingless type MMTV integration site family, member 5A; Ryk: Receptor like tyrosine kinase; CaMKII: Calmodulin dependent protein kinase 2; NFAT: Nuclear factor of activated T cells; hPMSCs: Human placental mesenchymal stem cells; EVs: Extracellular vesicles; hUC-MSCs: Human umbilical cord mesenchymal stem cells; LPS: Lipopolysaccharide; CFA: Complete Freund’s adjuvant; TRAF6: Tumor necrosis factor receptor associated factor 6; CCI: Chronic constriction injury; DMM: Destabilization of the medial meniscus; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; NGF: Nerve growth factor; DRG: Dorsal root ganglia; AMPK: AMP-activated protein kinase; Nrf2: Nuclear factor erythroid 2-related factor 2.

Table 2 Clinical trials evaluating mesenchymal stem cell-derived extracellular vesicle/exosome-based interventions for pain management

Study start year	Trial/study ID	Pain condition	Phase	Estimated enrollment	Intervention	Source
2024	NCT06431152	Knee osteoarthritis	Phase I	12	Intra-articular small EVs from umbilical cord MSCs	ClinicalTrials.gov
2024	NCT06466850	Osteoarthritis	N/A	20	Intra-articular MSC-derived exosomes	ClinicalTrials.gov
2021	NCT05060107	Knee osteoarthritis	Phase I	10	Single intra-articular MSC-derived exosome injection	ClinicalTrials.gov
2023	NCT04202783	Craniofacial neuralgia	Early phase (safety and efficacy)	100	Intravenous infusion of exosomes	ClinicalTrials.gov
2021	NCT04849429	Chronic low back pain (discogenic; intradiscal approach)	Phase I	30	Intradiscal injection of platelet-rich plasma with exosomes	[113]
2022 (approved year)	IRCT20210423051054N1	Knee osteoarthritis	Randomized, triple-blind clinical trial	31	Single intra-articular injection of placental MSC-EVs	[112]
-	ExoFlo interlaminar epidural safety study	Lumbar or cervical radiculopathy	Small open safety pilot study	10	Epidural injection of BM-MSC-EV isolate (ExoFlo); safety pilot	[114]

EVs: Extracellular vesicles; MSCs: Mesenchymal stem cells; N/A: Not applicable; MSC-EVs: Mesenchymal stem cell-derived extracellular vesicles; BM-MSC-EV: Bone marrow mesenchymal stem cell-derived extracellular vesicle.

Table 3 Translational barriers in clinical development of mesenchymal stem cell-derived extracellular vesicle therapies for pain

Challenges	Concerns
Study design	Lack of placebo/sham controls; open label designs dominate
	Limited inference of true clinical effect
Follow up duration	< 6 months endpoints
	Short for chronic pain assessment
Dosing and potency	No standardized unit of potency
	Prevents cross-trial comparison
Manufacturing	Heterogeneity in EV isolation protocols, and hence, unpredictable therapeutic consistency
	Inconsistent EV product quality
	Inconsistent therapeutic predictability
Regulatory	Unclear categorization (biologic vs cell-derived drug vs advanced therapy)
	Unclear oversight requirements

EVs: Extracellular vesicles.