Table 4.

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

HucMSCs-EVs Cargo	Target/Signaling	Conditions/Diseases	Actiona	Reference
miR-1263	Mob1/Hippo	Osteoporosis	BMSC apoptosis↓, bone homeostasis↑	[165,166]
CLEC11A	NF-κB, microglial activation	Osteoporosis	Osteoblasts ↑, osteoclasts↓, bone resorption↓, bone marrow fat accumulation↓	[167]
None reported	RUNX2, ALP, BMP-2, OCN	Fracture	Osteogenesis↑	[45,168,169]
None reported	HIF-1α, VEGF	Fracture	Angiogenesis↑	[169–171]
miR-23a-3p	PTEN / AKT	Fracture	Osteogenesis↑, angiogenesis↑	[169]
rhBMP-2	None reported	Fracture	Regeneration↑	[172–174]
None reported	AKT/ERK	Cartilage and intervertebral disc repair	Apoptosis↓, fibrosis↓	[171]
None reported	None reported	Periapical periodontitis	Osteoclast activity↓, inflammatory cell infiltration↓, alveolar bone regeneration↑	[45]
miR-223	NLRP3	OA	M1 polarization↓, M2 polarization↑, pyroptosis↓	[20]
None reported	NF-κB	OA	T-cell proliferation↓, inflammatory cascades↓	[184,185]
miR-100-5p	NOX4	OA	ROS↓	[186]
miR-7704	MMP13	OA	Matrix degradation↓	[187]
None reported	ITGB1/TGF-β/Smad2/3	OA	Chondrocytes protection↑	[188,189]
miR-181c-5p	SMAD7	OA	Chondrocytes↑	[192]
miR-23a-3p	PTEN/AKT	OA	Glycosaminoglycan and collagen II deposition↑	[193]
miR-29b-3p	FoxO3	OA	ECM synthesis↑	[195]
None reported	HIF-1α/VEGF	OA	Vascularization↑	[21,197]
None reported	RORγt, Foxp3	RA	Inflammation, immune tolerance↑	[200–202]
miR-45a	ATF2	RA	Synovial fibroblasts↓	[204]
miR-140-3p	SGK1	RA	Chondrocyte apoptosis↓	[205]
miR-132-3p	FoxO3	Muscle atrophy	Muscle atrophy↓	[207]
Follistatin	Myostatin, Smad2, AKT	Muscle injury, myotubes atrophy	Muscle regeneration↑, fibrosis↓	[208]
miR-29a-3p	PTEN/mTOR/TGF-β1	Achilles tendon injury	Tendon regeneration↑	[209]
None	None reported	OS	Proliferation↓	[212]

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