Table 3.

Molecular Mechanism of hucMSCs-EVs in Treating Different Diseases in the Nervous System

HucMSCs-EVs Cargo	Target/signaling	Conditions/Diseases	Actiona	Reference
None reported	NF-κB	TBI	M1/A1 polarization↓, M2/A2 polarization↑, cell apoptosis↓, neurogenesis↑	[18,46]
miR-21	NF-κB	TBI	Neuroinflammation↓, microglial activation↓	[58]
miR-146a-5p	Neurotoxic astrocyte pathways	TBI	The effects of neurotoxic astrocytes↓, neuronal integrity↑	[59,60]
PINK1	Mitophagy pathways	TBI	Mitophagy↑, oxidative stress↓	[61]
miR-146a-5p	IRAK1/TRAF6/NF-κB	Stroke	M2 polarization↑	[47]
miR-214-3p	GPX4, ACSL2	Stroke	Ferroptosis↓, mitochondrial integrity↑, oxidative stress↓, BBB integrity↑	[71]
miR-664a-5p	AAK1/ NF-κB	Stroke	Infarct volume↓, functional recovery↑	[72]
miR-29c, NEP	None reported	AD	Aβ degradation↑	[48]
miR-146a, TGF-β1	None reported	AD	M1 polarization↓, M2 polarization↑	[48,81]
functional mitochondria	None reported	AD	Membrane potential↑, ATP production↑, oxidative stress↓, apoptosis↓, neuronal survival↑	[83]
None reported	None reported	PD	the viability of dopaminergic neurons↑, olfactory function↑	[95,96]
None reported	LC3B-II/I, Beclin-1, p62	PD	α-synuclein aggregation ↓, apoptosis↓,	[98]
None reported	PI3K/Akt/NF-κB/NLRP3	PD	Pyroptosis↓	[96, 97]
None reported	SATB1/ Wnt/β-catenin	PD	Neurogenesis↑, neurite outgrowth↑, autophagy↓,	[96]
BDNF	MAP2, tau, Nrf2 antioxidant pathway	PD	Ferroptosis↓, oxidative damage↓	[100,101]
None reported	None reported	MS	Immune tolerance↑	[107,108]
miR-23a-3p	PI3K/Akt, Tbr1/Wnt	MS	Mature myelinating oligodendrocytes↑	[110]
None reported	MBP	MS	Demyelinated lesions↓, neurological function↑	[15,109]
None reported	Lag-3	MS	Immune cell proliferation↓, cytokine storm↓	[111]
None reported	A2bR/cAMP/PKA	SCI	M2 polarization↑	[120]
miR-21-5p	PDCD4	SCI	M2 polarization↑	[122]
miR-27a-3p	DLL4	SCI	Angiogenesis↑, functional recovery↑	[125]
None reported	NF200, MBP, GAP43, synaptophysin, PSD95	SCI	Remyelination↑, synaptogenesis↑, axonal growth↑,	[124,127–130]
miR-29b-3p	PTEN, Akt/mTOR	SCI	Nerve repair↑	[132]
None reported	ERK1/2	SCI	The proliferation and differentiation of NSCs↑	[128]
None reported	Bax, caspase-3, p75NTR, Bcl-2	SCI	Apoptosis↓	[124,126–129,131,134]
lncRNA-MALAT1	miR-22-3p/ SIRT1 /AMPK	SCI	Apoptosis↓	[134]
None reported	ET-1, ZO-1, β-catenin, occludin, claudin-5	SCI	BSCB integrity↑	[135,136]
miR-501-5p	MLCK	SCI	Vascular leakage↓	[136]
miR-138	NLRP3-caspase1, Nrf2-keap1	SCI	Oxidative stress↓, glial scarring↓	[137]
miR-21	PI3K/Akt/mTOR, MAPK	PNI	SC activation↑, axonal elongation ↑, remyelination↑	[145,146]
miR-23b-3p	Fbxo32, Trim63	PNI	Muscle mass and function↑	[151]
miR-124	CDK4, CDK6	GBM	Apoptosis↑	[153]

Notes: ^a ↑ indicates promotion or upregulation; ↓ indicates inhibition or downregulation.