Table 1 Studies indicating Nrf2 role in therapeutic effects of exosomes derived from various stem cell sources

BMSC/

SD rat

–

CD9, CD63, TSG101

Diabetic wound

Exosomes improved the formation of EPC tubes, sped up the healing process, and reduced inflammation in diabetic wounds. By utilizing a Nrf2 activator, the therapeutic advantages of the exosomes were enhanced by Nrf2 activation

Nrf2 shRNA

[45]

ADSC/SD rat

miR-130a-3p (transfection)

CD9, CD63, TSG101

Diabetic peripheral neuropathy

miR-130a-3p delivery through ADSC-derived EVs activated Nrf2/HIF1α/ ACTA1 pathway by DNMT1 suppression to improve diabetic peripheral neuropathy through inhibiting schwann cells apoptosis

Nrf2 shRNA

[67]

ADSC/ C57BL/KsJ db/m mice

–

CD9, CD63, CD81

Diabetic nephropathy

Exosomes effectively alleviated inflammation and oxidative stress caused by high glucose in podocytes by upregulation of FAM129B and reactivation of the Nrf2-HO-1 pathway

HO-1 siRNA

[60]

hUC-MSC/ Human

circHIPK3 (transfection)

CD63, CD81, TSG101

Diabetes mellitus

circHIPK3 overexpressing exosomes provided a protective effect against cell injuries induced by high glucose and promoted angiogenesis in diabetic wounds by the direct inhibition of miR-20b-5p activity which leads to upregulation of Nrf2 and VEGFA expression

–

[74]

BMSC

circ-ITCH

(transfection)

CD63, CD9, TSG101

Diabetic foot ulcers

Exosomal circ-ITCH blocked ferroptosis and stimulated the HUVECs angiogenesis by Nrf2 pathway activation through the recruitment of TAF15 protein and ultimately accelerated the healing process of wound

Nrf2 shRNA

[91]

ADSC/ Human or rat

Nrf2 (transfection)

CD4, CD63, TSG101

Diabetic foot ulcer

Exosomes extracted from Nrf2-overexpressing stem cells improved foot ulceration in diabetic rats

–

[87]

BMSC/ C57BL/6 J mice

–

CD63, TSG101

Respiratory distress syndrome

Exosomes mitigated sepsis-induced AECII apoptosis through restoring the mitochondrial dysfunction mediated by Nrf2

ML385 Nrf2 inhibitor

[140]

ADSC/ Human

miR-125b-5p

CD63, CD9, TSG101

Sepsis lung injury

Delivery miR-125b-5p via exosomes reduced inflammation-induced ferroptosis in PMVECs and protected lung damage by regulation of Keap1/Nrf2/GPX4 axis

–

[133]

hUC-MSC/ Human

miR-199a-5p (transfection)

HSP70, CD63, TSG101

Acute lung injury

Exosomes enhanced the Nrf2 expression and translocation into the cell nucleus by transporting miR-199a-5p and interacting with CAV1 which led to upregulation of antioxidant enzymes expression within lung cells and regulation of oxidative stress

–

[134]

hAMSC/ Human

Nrf2 (transfection)

CD9, CD63, CD81

Acute lung injury

sEVs obtained from Nrf2-overexpressing hAMSCs protected against LPS -induced lung injury through preventing the NLRP3 activation and promoting the M2 macrophages polarization

Nrf2 siRNA

[126]

BMSC/ C57BL/6 mice

circ_0072464 (transfection)

CD63, CD81, TSG101

Intervertebral disc degeneration

circ_0072464 transported by EVs increased the levels of Nrf2 expression by competitive binding with miR-431 which led to ferroptosis suppression in nucleus pulposus cells and IDD alleviation

Nrf2 shRNA

[115]

BMSC/Human

–

CD63, CD81

Intervertebral disc degeneration

Exosomes restored the down-regulated antioxidant response system by modulation of the Keap1/ Nrf2 axis in degenerating nucleus pulposus cells

ML385 Nrf2 inhibitor, Nrf2 siRNA

[114]

ADSC/SD rat

–

CD63, CD81, HSP-70

Dexamethasone-induced bone loss

Exosomes reduced oxidative stress and apoptosis by regulation of Nrf2/HO-1 expressions and prevented the progression of glucocorticoid-induced osteoporosis

Nrf2 siRNA

[11]

hUC-MSC/Human

–

TSG101, CD9, CD63

Non-alcoholic steatohepatitis

Exosomes exerted anti-lipid deposition, anti-oxidative stress and anti-inflammatory effects through activation of Nrf2/NQO-1 pathway

ML385 Nrf2 inhibitor

[185]

hUC-MSC/ Human

miR-24-3p (transfection)

CD9, CD63, CD81

Nonalcoholic fatty liver disease

Delivery of miR-24-3p by exosomes effectively targeted Keap-1, leading to the inhibition of lipid synthesis and NF-kB signaling pathways, and improvement of Nrf2 activation in NAFLD

Keap1 siRNA

[179]

BMSC/ C57BL/6 mice

Baicalin (transfection)

CD9, CD63, CD81, TSG101

Acute liver injury

Exosomes derived from Baicalin-pretreated MSC exhibited a protective effect on liver function and activated the Keap1- Nrf2 pathway by P62, which prevents ROS generation and inhibits ferroptosis induced by lipid peroxides

ML385 Nrf2 inhibitor

[172]

iPSCs–MSC/Human

–

–

Myocardial injury

Exosome led to promoted cardiomyocyte viability, improved cardiac function, reduced infarction ratio, and suppressed oxidation levels by activation Akt/Nrf2/HO-1 pathway

LY294002 PI3K/Akt inhibitor

[159]

BMSC/ C57BL/6 mice

FNDC5 (transfection)

CD63, CD81, ALIX

Myocardial infarction

Exosomes derived from FNDC5-preconditioned BMSCs played a protective role against MI through anti-inflammatory effects and polarization of macrophage which partly reduced NF‐κB and upregulated Nrf2/ HO-1 Axis

SnPP HO-1 inhibitor

[46]

BMSC/SD rat

Nrf2

(transfection)

CD63, CD81, CD9, TSG101, Alix

Atrial fibrillation

Lv-Nrf2 exosomes delivery suppressed arrhythmias induced by atrial fibrillation, myocardial apoptosis, fibrosis and inflammation by the Nrf2/HO-1 axis

–

[24]

ADSC/

SD rat

–

CD9, CD63, HSP70

MTX-induced neuronal damage

Exosomes inhibited oxidative stress triggered by MTX in hippocampus neurons by Nrf2-ARE activation

ML385 Nrf2 inhibitor 

[196]

BMSC/Mouse

–

CD63

Delayed neurocognitive recovery (dNCR)

Exosome improved cognitive function by suppressing hippocampus ferroptosis through activation of the SIRT1/Nrf2/HO-1 axis in dNCR aged mice

EX-527 SIRT1 inhibitor

[197]

hUC-MSC/Human

–

Flotillin-1, CD63, TSG101

LPS/H2O2-induced neuroinflammation

Exosomes blocked the Nrf2/NF-κB p65/NLRP3 signaling pathway to attenuate oxidative stress and neuroinflammation, as well as increase a shift microglia phenotype from pro- to anti-inflammatory

ML385 NRF2 inhibitor

[237]

ADSC/C57BL/6 mice

circAkap7

(transfection)

CD9, CD63, TSG101

Cerebral ischemic injury

Exosome-circAkap7 provided protection against ischemic damage through enhancing ATG12-mediated autophagy and alleviated oxidative stress via increasing nuclear transcription of Nrf2 by absorbing miR-155-5p

Nrf2 siRNA

[194]

BMSC/SD rat

miR-194

(transfection)

CD63, TSG101

OGD/R

Exosomes loaded with miR-194 alleviated damage caused by OGD/R by suppressing expression of Bach1 and promoting the Nrf2/HO-1 axis activation via delivery of miR-194 to endothelial cells of brain vessels, which led to the ferroptosis reduction in these cells following hypoxic-ischemic brain injury

–

[193]

hNSC/Human

–

CD9, CD63, CD81

Hypoxia-reperfusion injury

Coculture of human NSCs-derived EVs with neurons inhibits the apoptosis of the neurons by inducing the translocation of NRF2 to neuronal nuclei, regulating the expression of oxidative stress-induced kinases

–

[195]

BMSC/Wistar rat

miR-23b (transfection)

CD81, CD63, TSG101

Intracerebral hemorrhage

Exosomal miR-23b ameliorated oxidative stress and neuroinflammation in ICH. PTEN acts as a target gene of miR- 23b by regulation of the Nrf2 signaling pathway and activation of NLRP3 inflammasome

–

[198]

T-MSCs human

miR-100-5p

TSG101, CD9, HSP70

Parkinson disease

Exosomes enriched with miR-100-5p provide a protective role against the degeneration of dopamine neurons and contribute to the preservation of the function of nigrostriatal system, improvement of motor impairments and mitigation of oxidative stress by modulating the Nox4-ROS-Nrf2 axis

ML385 Nrf2 inhibitor

[199]

hUC-MSC/Human

–

CD63, CD81

Oxidative stress-induced skin injury

Exosomes attenuated oxidative stress-induced skin damage by decreasing ROS production and improving the antioxidant capacities by the Nrf2 defense system regulation

ML385 Nrf2 inhibitor, Nrf2 siRNA

[191]

ADSC/Rat

–

CD9, CD63, CD81

Ultraviolet B-mediated Photoaging

Exosomes prevented ROS generation and DNA damage induced by UVB through activating the Nrf2 pathway and promoting protective antioxidants expression

–

[236]

Placenta- MSC/Human

miR-21 (transfection)

CD63, CD9, HSP70

Aging-related

oxidative damage

Exosomes containing miR-21 upregulated the expression of the PTEN/PI3K-Nrf2 axis in senescent CD4 + T cells, improved their antioxidant capabilities, thereby attenuating age-related immunological dysfunction

PTEN inhibitor bpV (HOpic)

[214]

hESC/Human

miR-200a

CD9, CD63, TSG-100

Aged mouse skin pressure ulcer model

Exosomes accelerated wound healing and improved angiogenesis by rejuvenating endothelial senescence. In addition, they exerted the anti-aging impacts through the transfer of miR-200a to senescent endothelial cells and Nrf2 signaling activation

Brusatol Nrf2 inhibitor

[47]

PDLSC/Human

miR-141-3p

CD9, CD63, CD81, TSG101

High glucose induced senescence

Exosomes exhibited anti-aging effects by miR-141- 3p delivery to reduce KEAP1 expression and activate the Nrf2 antioxidant pathway

ML385 Nrf2 inhibitor

[30]

Placenta- MSC/Human

miR-200a-3p

TSG101 ALIX, CD9, CD63

AKI model induced by IRI

miRNA-200a-3p delivered by MSC-EVs activated the Keap1-Nrf2 pathway in TECs to exert antioxidant effects, which helps restore renal function by regulating mitochondrial structure and function

-

[225]

hUC-MSC/Human

–

CD9, CD44, CD63, CD73

AKI model induced by IRI

MSC-sEVs have the potential to alleviate AKI caused by I/R and can assist in balancing oxidative stress and antioxidative responses by enhancing the activation of Nrf2/ARE

–

[223]

hUC-MSC/Human

ACE2 (transfection)

CD9, CD63, TSG101

AKI model induced by IRI

MSC-ACE2-sEVs could protect the kidney against I/R injury, and this effect could be attributed to Nrf2/HO-1 axis activation

–

[226]