Table 2.

Summary of researches on EVs involved in in vivo wound repair

Wound type	Animal model	EVs type	Cargo	Target	Function	References
Acute wound	Rat model of the skin-deep second-degree burn wound	HucMSC-derived EVs (30–100 nm)	–	Wnt/β-catenin	Proangiogenic effect↑	[94]
	Rat skin burn model	HucMSC-derived EVs	–	Wnt4	Heat stress-induced apoptosis↓	[95]
	Deep second-degree burn mice model	Blue light-treated MSC-derived EVs	miR-135b-5p miR-499a-3p	MEF2C	Proangiogenic ability↑	[89]
	Severe burn rat model	HucMSC-derived EVs	miR-181c	Toll-like receptor 4	Burn-induced inflammation↓	[96]
	Rat full-thickness cutaneous wounds model	UCB-MSC-derived EVs	miR-21-5p miR-125b-5p	TGF-β receptor type II and TGF-β receptor type I	Anti-myofibroblast differentiation↑	[91]
	Mouse full-thickness cutaneous wounds model	UCMSC-derived EVs (75.66 nm)	–	–	Recruitment of fibroblasts↑ Cutaneous nerve regeneration↑	[97]
	Mouse full-thickness skin defects model	HucMSC-derived EVs (85% range from 20 to 200 nm)	–	Inhibiting nuclear translocation of apoptosis-inducing factor Upregulating poly ADP ribose polymerase 1 (PARP-1) and poly (ADP-ribose)	Epidermal re-epithelialization↑ Dermal angiogenesis↑	[98]
	Mouse skin wound model	BMSCs overexpressed with miR-126 EVs (Exo-miR-126, 30–200 nm)	miR-126	Targeting phosphoinositol-3 kinase regulatory subunit 2 to activate the PI3K/Akt signalling pathway	Newly formed capillaries↑	[24]
	Rat skin wound model	hiPSC-MSC-derived EVs	–	–	Collagen synthesis↑ Angiogenesis↑	[47]
	Rat skin wound model	HucMSC-derived EVs	14-3-3ζ proteins	Wnt/β-catenin signaling	Cutaneous regeneration	[99]
	Mouse retinal laser injury wound model	HucMSC-derived EVs (40–100 nm)	–	Downregulation of monocyte chemotactic protein-1	Apoptosis↓ Inflammatory responses↓	[100]
	Mouse full-thickness dermal wound injury model	FDMSC-derived EVs	–	Notch signaling pathway by Jagged 1	Adult dermal fibroblast cell motility and secretion ability↑	[101]
	Mouse full-thickness dorsal wound model	ADMSC-derived EVs	–	Regulating the ratios of collagen type III to type I, TGF-β3 to TGF-β1 and MMP-3 to TIMP-1	ECM reconstruction↑	[102]
	Mouse full-thickness dorsal wound model	ADMSC-derived EVs	miR-125a-3p	PTEN	Angiogenesis↑	[103]
	Corneal epithelial wound model	HucMSC-derived EVs	miR-21	PTEN PI3K/Akt signaling pathway	Corneal wound repair↑	[104]
	Mouse excisional full-thickness wound model	ADMSC-derived EVs (113.6 nm)	miR-192-5p	miR-192-5p/IL-17RA/Smad axis	Anti-fibrotic properties↑	[105]
	Mouse full-thickness skin wound model	TSG-6 overexpressed MSC-derived EVs	–	–	Scar pathological injury↓ Collagen deposition↓	[106]
	Mouse full-thickness wound model	ADMSC-derived EVs	–	–	Collagen expression↓ Scar formation↓	[107]
	Mouse skin-defective wound model	BMSC-derived EVs (20–200 nm)	miR-223	PKNOX1	M2 polarization of macrophages	[108]
	Mouse full-thickness skin defect model	HucMSC-derived EVs (30–150 nm)	miR-21 miR-23a miR-125b miR-145	Transforming growth factor-β/Smad2 signaling pathway	Myofibroblast formation↓	[109]
	Murine hind limb ischemia model	EVs released from hP-MSCs by NO stimulation	VEGF miR-126	–	Angiogenic processes↑	[110]
	Diabetic rat wound model	ATV pretreated BMSC (ATV-derived EVs, 80–120 nm)	miR-221-3p	Akt/eNOS signaling pathway	Angiogenesis effect↑	[111]
Chronic wound	Diabetic rat wound model	HucMSC-derived EVs (30–150 nm)	–	–	VEGF and TGF-β1↑	[112]
	Diabetic mouse cutaneous wound model	HucMSC-derived EVs (30–150 nm)	–	–	Oxidative stress↓ Angiogenesis↑	[113]
	Eczema mouse wound model	MSC-derived EVs	–	–	Inflammatory cell infiltration↓ Vascular formation↑	[114]
	Diabetic mouse wound model	Hypoxic ADMSC-derived EVs	Upregulated miR-21-3p, miR-126-5p, miR-31-5p Downregulated miR-99b and miR-146-a	PI3K/Akt signaling pathway	Diabetic wounds healing↑ Inflammation↓	[115]
	Diabetic rat cutaneous wound model	LPS‐preconditioning of HucMSC-derived EVs (40–90 nm)	let-7b	let-7b/TLR4 pathway[116]	Regulatory abilities for macrophage polarization	[116]
	AD-like chronic allergic dermatitis mouse model	ADMSC-derived EVs	–	Facilitating the de novo synthesis of ceramides	Epidermal barrier functions↑	[117]
	Rat diabetic foot ulcers model	Linc00511-overexpressing ADMSC-derived EVs	–	Suppressing PAQR3-induced Twist1 ubiquitin degradation	Angiogenesis↑	[118]
	Diabetic rat wound model	hBMSC-derived EVs hBMSC-MT-derived EVs (30–150 nm)	–	PTEN/Akt pathway	Regulating macrophage M1 and M2 polarization	[26]
	SD rat skin photoaging model	ADMSC-derived EVs (30–150 nm)	–	–	Type I collagen↑ Type III collagen, MMP-1, and MMP-3↓	[119]
	Wound model	ADMSCs overexpressing Nrf2-EVs	–	–	Granulation tissue formation↑ Angiogenesis↑ Growth factor expression↑ Oxidative stress-related proteins↓	[120]
	Diabetic mouse cutaneous wound model	BMSC-derived EVs (50–150 nm)	lncRNA KLF3-AS1	miR-383, VEGFA	Angiogenesis↑	[121]
	Diabetic rat wound model	BMSCs preconditioned by deferoxamine-derived EVs (50–150 nm)	miR-126	PTEN PI3K/Akt signaling pathway	Wound healing↑ Angiogenesis↑	[122]
		HucMSC-derived EVs (40–100 nm)	–	Downregulation of monocyte chemotactic protein-1	Apoptosis↓ Inflammatory responses↓	[100]

EVs extracellular vesicles, HucMSC human umbilical cord mesenchymal stem cell, MSC mesenchymal stem cell, UCB-MSC umbilical cord blood mesenchymal stem cell, UCMSC umbilical cord mesenchymal stem cell, ADP adenosine diphosphate, BMSC bone marrow mesenchymal stem cell, Exo exosome, hiPSC human-induced pluripotent stem cells, FDMSC fetal dermal mesenchymal stem cell, ADMSC adipose-derived mesenchymal stem cell, MMP matrix metalloproteinases, PTEN phosphatase and tensin homolog deleted on chromosome 10, TSG-6 tumor necrosis factor alpha-stimulated gene 6, PKNOX1 homo sapiens PBX/knotted 1 homeobox 1, Smad Drosophila mothers against decapentaplegic proteins, hP-MSC human placenta-derived mesenchymal stem cell, ATV atorvastatin, LPS lipopolysaccharide, PAQR3 progestin and adipoQ receptor 3, hBMSC human bone marrow mesenchymal stem cell, IL interleukin, VEGFA vascular endothelial growth factor A, eNOS endothelial nitric oxide synthase, TLR toll-like receptor, AD atopic dermatitis