Table 1.

Current applications of MSC-EVs in treating degenerative conditions. In vitro and in vivo efficacy and promotion of cellular functions to facilitate tissue repair.

EV Source	Model	Results	Reference
Osteoarthritis
Chondrocyte-derived exosomes (CC-Exos)	In vitro, chondrocyte	1.Enhanced cartilage progenitor cell expansion and increased expression of chondrogenesis-related factors.	[28]
		2.Promoted collagen deposition, reduced vascular ingrowth, and developed into cartilage.
BMSC-derived exosomes (BMSC-Exos)	In vivo, anterior cruciate ligament transection (ACLT) + destabilization of the medial meniscus (DMM) OA model	1.Mitigated cartilage damage by targeting proinflammatory factors with miR-135b.	[29,30]
		2.Inhibited chondrocyte apoptosis and MMP expression by modulating Drp1-mediated mitophagy.
Embryonic MSC-derived exosomes (EMSC-Exos)	In vitro, chondrocyte	1.Maintained chondrocyte phenotype with increased collagen type II synthesis and reduced ADAMTS5 expression.	[31]
		2.Effects linked to adenosine-triggered protein kinases, TGF-β, and IGF activation.
Human synovial MSC-derived exosomes (hSMSC-Exos)	In vitro, chondrocyte	Promoted chondrocyte proliferation and migration by upregulating Wnt5a, activating YAP signaling pathways, and suppressing extracellular matrix formation.	[32,33]
ADSC-derived exosomes (ADSC-Exos)	In vitro, OA chondrocyte	Reduced senescence-associated β-galactosidase activity and the secretion of inflammatory mediators from OA osteoblasts and catabolic mediators from OA chondrocytes.	[34]
IPFP-derived exosomes (IPFP-Exos)	In vitro, chondrocyte	Elevated levels of Sox-9, aggrecan, and type II collagen expression, more effective than IPFP-Exos pretreated with kartogenin.	[35]
ADSC-Exos	In vitro, chondrocyte	Increased periosteal cell proliferation and chondrogenic capacity linked to miR-145 and miR-221, respectively.	[36]
IPFP-Exos	In vivo, DMM-induced OA animal model	1.Enhanced chondrocyte autophagy through miR-100-5p inhibition of mTOR.	[37]
		2.Intra-articular administration of antagomir-100-5p protected cartilage from deterioration and improved gait by repressing chondrocyte apoptosis through the mTOR-autophagy pathway.
hSMSC-Exos	In vivo, ACLT-induced OA model	hSMSC-Exos overexpressing miR-140-5p augmented cartilage regeneration and slowed knee OA progression in a rat model.	[38]
BMSC-Exos	In vivo, collagenase-induced OA mouse model	BMSC-Exos overexpressing miR-92a-3p suppressed cartilage degradation by directly targeting WNT5A and preserving articular chondrocyte function.	[39]
BMSC-Exos	In vivo, ACLT + DMM OA surgery model	TGF-β1 promoted chondrocyte proliferation by modulating Sp1 through miR-135b sourced from BMSC-Exos, aiding cartilage restoration.	[40]
Cardiovascular disease
HIF-1α engineered MSC-derived EVs (HIF-1α-EVs)	In vitro: cardiomyocytes and endothelial cells under hypoxia and serum deprivation (H/SD); In vivo: Sprague Dawley rats with acute myocardial infarction (AMI)	1.Reduced cardiomyocyte apoptosis and enhanced endothelial cell angiogenesis.	[81]
		2.Reduced fibrosis and improved cardiac function in rats.
		3.Enhanced effects with RGD-biotin hydrogels.
Human bone marrow MSC-derived EVs (MSC-EVs)	In vitro: human umbilical vein endothelial cells; In vivo: rat MI model	1.Promoted endothelial cell proliferation, migration, and tube formation in vitro.	[84]
		2.Enhanced blood flow recovery, reduced infarct size, and preserved cardiac performance in vivo.
MSC-Exos derived from MSCs pretreated with ischemic rat heart extract (MSCE-Exos)	In vitro: human umbilical vein endothelial cells (HUVECs)	1.Enhanced HUVEC proliferation and migration.	[85]
		2.Proteomic analysis revealed upregulation of angiogenesis-related proteins, including DMBT1.
		3.DMBT1 delivery via MSCE-Exos was crucial for angiogenesis, with silencing of DMBT1 impairing HUVEC activity.
		4.Ischemic heart extracts revealed increased levels of IL-22 and subsequent upregulation of VEGF and DMBT1 in MSCs, which enhanced the angiogenic effects of the derived exosomes.
Human umbilical cord MSC-derived exosomes (hucMSC-Exos)	In vivo: AMI rats; In vitro: hypoxic H9C2 cells	1.miR-19a was transferred, which offered protection for cardiomyocytes through the reduction of apoptosis and infarct size.	[86]
		2.miR-19a targeted SOX6; inhibition of SOX6 reduced hypoxic damage.
		3.Enhanced cardioprotection through the activation of AKT and inhibition of JNK3/caspase-3 pathway.
Mesenchymal stem cell–derived exosomes (MSC-Exos)	In vivo: mouse model of myocardial ischemia/reperfusion (I/R); In vitro: macrophage polarization studies	1.Reduced infarct size and inflammation postmyocardial I/R.	[87]
		2.Facilitated macrophage polarization from M1 to M2, improving cardiac recovery.
		3.miR-182 targeted TLR4, influencing macrophage polarization and reducing inflammation.
MicroRNA-1-transduced MSCs (MSC(miR-1))	In vivo: C57BL/6 mice with MI	1.Enhanced differentiation of transplanted MSCs into cardiomyocytes in the infarcted zone.	[88]
		2.Improved cardiac function.
		3.Increased cell survival and cardiomyogenic differentiation.
Age-related macular degeneration
Human umbilical cord MSC-derived exosomes (hucMSC-Exos)	In vitro: RPE cells; In vivo: laser-induced CNV and subretinal fibrosis model in mice	1.Intravitreal injection of hucMSC-Exo reduced subretinal fibrosis and CNV.	[94]
		2.Suppressed RPE cell migration and promoted mesenchymal–epithelial transition via miR-27b.
		3.miR-27b targeted HOXC6, inhibiting the EMT process induced by TGF-β2.
Adipose-derived MSC exosomes (Ad-MSC-Exos)	In vivo: streptozotocin-induced diabetes in rabbits	1.Improved retinal structure, with SC and IO routes showing well-defined retinal layers similar to normal retina.	[95]
		2.IV route resulted in less organized retinal layers.
		3.Significant increase in micRNA-222 expression associated with retinal repair and regeneration.
MSC-derived exosomes (MSC-Exos)	In vivo: mouse models of photoreceptor loss (MNU-induced and Pde6bmut)	1.Intravitreal MSC transplantation and exosomal transplantation counteracted photoreceptor apoptosis and alleviated retinal degeneration.	[101]
		2.Effects sustained for 1–2 months after a single injection.
		3.miR-21 targeted Pdcd4, protecting photoreceptors and preventing retinal dysfunction.
Human bone marrow–derived MSCs (hBMSCs)	In vitro: Cultured hBMSCs	1.Overexpression of the miR-183/96/182 cluster upregulated neuroretinal genes such as OTX2, NRL, PKCα, and recoverin.	[102]
		2.Ectopic expression of the miR-183 cluster increased CRX and rhodopsin levels at mRNA and protein levels, suggesting initiation of photoreceptor cell differentiation.
		3.No morphological changes in cells despite gene expression alterations.
Alzheimer's disease
Human adipose tissue-derived MSC exosomes (ADSC-Exos)	In vitro: N2a neuroblastoma cells	1.Carried enzymatically active neprilysin (NEP), a pivotal β-amyloid-degrading enzyme.	[118]
		2.Transferred NEP into N2a cells, significantly reducing both secreted and intracellular Aβ levels.
		3.More effective than bone marrow–derived MSC exosomes.
Mesenchymal stem cell–derived EVs (MSC-EVs)	In vivo: APP/PS1 mouse model of Alzheimer's disease	1.Reduced inducible nitric oxide synthase (iNOS) mRNA and protein levels in primary cultured neurons and APP/PS1 mice.	[119]
		2.Improved cognitive behaviors and rescued synaptic transmission and long-term potentiation in the hippocampal CA1 region.
Mesenchymal stem cells and cell–derived EVs (MSC-EVs)	In vitro: Transwell cocultures with rat hippocampal neurons	1.Protected hippocampal neurons from amyloid-beta oligomer (AβO)-induced oxidative stress and synapse damage.	[120]
		2.Protection involved internalization and degradation of AβOs, release of catalase-containing EVs, and secretion of anti-inflammatory cytokines and growth factors.
Human Wharton's jelly MSC-derived EVs (hMSC-EVs)	In vitro: Primary hippocampal cultures exposed to AβOs	1.Internalized by hippocampal neurons, enhanced in the presence of AβOs.	[121]
		2.Protected neurons from oxidative stress and synaptic damage induced by AβOs.
		3.Neuroprotection mediated by catalase EVs, abolished by catalase inhibition.
Mesenchymal stem cell–derived exosomes (MSC-Exos)	In vivo: mouse model of Alzheimer's disease	1.Stimulated neurogenesis in the subventricular zone.	[123]
		2.Alleviated beta-amyloid 1-42-induced cognitive impairment in Morris water maze and novel object recognition tests.
Human umbilical cord MSC-derived exosomes (hucMSC-Exos)	In vivo: AD mouse model; In vitro: BV2 microglial cells	1.Alleviated neuroinflammation and reduced amyloid-beta deposition in AD mouse models.	[125].
		2.Improved cognitive function and modulated microglial activation.
		3.Regulated inflammatory cytokine levels both in vivo and in vitro.
Allogenic human adipose MSC-derived exosomes (ahaMSCs-Exos)	Phase I/II clinical trial in patients with mild to moderate Alzheimer's disease	1.No adverse events were reported during the trial.	[129]
		2.The medium-dose arm exhibited significant improvement in cognitive function, as measured using ADAS-cog and Montreal Cognitive Assessment scores.
		3.Although no significant changes in amyloid or tau levels were observed, a reduction in hippocampal volume loss was noted in the medium-dose arm.

Choroidal Neovascularization (CNV); cone-rod homeobox (CRX); subconjunctival (SC); and intraocular (IO); yes-associated protein (YAP).