Table 7.

EV treatment paper.

Author/Year	Model/Disease	EV source	Transfer parameters	Clinical & biological evidences	Mitochondrial mechanisms modulation

Gai 2024 [55]	C57BL/6J Mice IRI Stroke	MSC cells Mice Allogenic	Dose: 100 μg of EV proteins Administration: intra-nasal	↓ hypoxia-ischemia-induced injury ↓ neuronal damage ↓ infarct size (≈40 % reduction HI-EV vs. HI, ≈20 % reduction H2S-EV vs HI-EV)	↑ anti-ox (Nrf2, PARK7, PRDX1, PRDX2) ↑ mito quantity (mtDNA) ↑ fusion (mfn1 and mfn2 mRNA)
Wu 2023 [56]	Balb/c Mice IRI stroke	Hypoxic neurons cells Mice Allogenic	Dose: 10⁸ EV Administration: stereotactic microinjection Sites: cortex or nasal drops	↓ cerebral infarction volume (≈45 % vs. vehicle) ↑ neuronal neurite survival ↑ neuronal integrity ↑ neuroprotection	↓ mitochondria-associated apoptosis
Ikeda 2021 [57]	C57BL/6 Mice IRI cardiac	Induced cardiomyocyte cells Human Xenogeneic	Dose: 10⁸ EV Administration: Injection Site: peri-infarct region	↑ ejection fraction (≈20 % vs. vehicle) ↑ restoration of intracellular bioenergetics and contractile property ↑ post-MI cardiac function improvement	↑ mito biogenesis (PGC-1α)
Lu 2021 [58]	C57BL/6 Mice IRI liver	UC-MSC cells Human Xenogeneic	Dose: 10⁹ EV Administration: IV Site: tail	↓ liver IRI ↑ hepato-protection & ↓ liver damage ↓ NETs formation	↑ fusion (Mfn1) ↓ oxidative stress (mtROS)
Zhao 2021 [59]	C57BL/6 Mouse IRI renal	MSC cells Human and mouse Allogenic/Xenogeneic	Dose: 2*10⁷ EV Administration: IV Site: tail	↓ kidney inflammation ↓ renal lesion formation	↑ OXPHOS ↓ mtDNA and mitochondrial damage ↑ mito biogenesis (restoring TFAM protein and stabilizing the TFAM-mtDNA complex)
Yao 2019 [60]	Sprague-Dawley rats IRI liver	UC-MSC cells Human Xenogeneic	Dose: 10 mg/kg EV Administration: IV Site: tail	↑ hepatoprotection ↓ liver damage ↓ mRNA levels of IL-1β, IL-6, TNF-α, C-C motif ligand 12, IFN-κ, and TLR4	↑anti-ox (MnSOD) ↓ respiratory burst ↓ ROS (CellRox Deep Red, mitosox)
Bao 2022 [108]	C57BL/6J Mice Sepsis associated coagulopathy	Primary neutrophils cells Mice Allogenic	Dose: 2*10⁵ EV Administration: IV Site: tail	↓ mortality 40 % with EV treatment vs ↓ mortality 20 % with vehicle treatment at 70 h ↑ neutrophil-mediated prevention of DIC ↑ antithrombotic function of neutrophils ↓ endothelial dysfunction ↓ DIC severity	↑anti-ox (SOD2) mediated endothelial protection ↓ endothelial ROS accumulation
Zheng 2021 [109]	Sprague-Dawley Rat Sepsis	MSC cells Rat Allogeneic	Dose: 2*10⁷ EV Administration: IV Site: tail	↓ mortality (from 56 % to 25 %) ↓ intestinal barrier dysfunction	↑ fusion (mfn2) ↑ mito biogenesis (PGC-1α)
Yao 2024 [117]	C57BL/6J Mice Wound healing	ADSCs cells Human Xenogeneic	Dose: 3*10⁸ EV Administration: hydrogel MNP Site: skin	↓ wound healing time (≈5 day less vs. vehicle) ↑ macrophage polarization (M2 subtype)	↑ MMP ↑ ATP levels ↓ ROS (Cell Rox probe)
Zhuang 2024 [118]	C57BL/6 Mice Aging	Metformin treated MSC cells Human Xenogeneic	Dose: 10¹⁰ EV Administration: hydrogel wound beds Site: skin	↑ aged skin repair ↓ cellular senescence	↑ ATP production ↑ OXPHOS ↑ mitophagy (LC3 II)
Chen 2024 [119]	C57BL/6 Mice Aging	Plasma Mice Allogenic	Dose 36 μg of EV proteins Administration: IV Site: not specified	↓ age-associated functional decline ↓ senescence ↑ tissue regeneration ↑ lifespan	↑ mito biogenesis (PGC-1α)
Liang 2024 [140]	Sprague-Dawley Mice Erectile disfunction	PC-12 cells Rat Xenogeneic	Dose: 10⁸ MVs Administration: IC Site: Corpus cavernosum	↑ erectile function ↓ ferroptosis ↓ apoptosis	↓ oxidative stress marker (MDA)
Shen 2024 [141]	C57BL/6 Mice Autoimmune Hepatitis	MSC cells Human Xenogeneic	Dose: 3*10¹⁰ MVs Administration: IP	↓ liver injury & ↑ liver protection ↑ glycolysis inhibition ↓ CD4⁺ T-cell activation ↓ mRNA IFN-γ, TNF-α, and IL-2	↓ OXPHOS
Tolomeo 2024 [142]	Pig Graft quality transplant for IRI	MSC cells Pig Allogenic	Dose: 10¹¹ MVs Administration: into the solution of heart perfusion machine	↑ myocardial viability ↓ apoptosis ↓ IL-1ra, IL-2 and IL-6	↓ anti-ox (SOD, CAT, GPX) ↓ oxidative stress (carbonylated proteins) ↓ mitochondrial cristae loss ↓ mitochondrial swelling
Cao 2022 [143]	BALB/c Mice Solid tumors	Dendritic cells Mice Allogenic	Dose: 80 μg EV proteins Administration: IV Site: tail	↓ tumor size (≈80 % reduction vs. vehicle) ↑ T cell activation ↑ immunogenic cell death in tumor cells ↑ immune responses against primary, distant tumors and metastases tumors ↑ efficient eradication of primary, distant and metastases tumors ↓ cancer stem cells	Not investigated
Lu 2022 [144]	C57BL/6 Mice Cardiac hypertrophy	Hypoxic MSC cells Human Xenogeneic	Dose: 10⁹ EV Administration: IV Site: tail	↑ hepatoprotective effects ↓ NETs formation (suppressed by hUC-MSC-EV) ↓ liver IRI severity	↓ mitochondrial ROS (mitosox) ↑ mitochondrial fusion in neutrophils (Mfn2) ↓ cytokine release from neutrophils (IFN-γ, IL-6 and TNF-α)
Li 2022 [145]	C57BL/6 Mice Liver Fibrosis	Plasma Mice Allogenic	Dose: 4*10⁸ EV Administration: IV Site: tail	↓ liver fibrosis progression ↑ collagen synthesis and degradation regulation ↓ HSC activation	↑ anti-ox (GSH levels) ↓ ROS (CMXROS)
Dutra Silva 2021 [146]	C57BL/6 Mice ARDS	BM-MSC cells Human Xenogeneic	Dose: 98.3 μg of EV proteins Administration: IV Site: tail	↑ barrier integrity ↑ barrier integrity with ARDS plasma ↓ LPS-induced inflammation	↑ in vivo mitochondrial respiration (OCR)
Morrison 2017 [147]	C57BL/6 Mouse ARDS	MDMs cells Human Xenogeneic	Dose: not specified Administration: intra-nasal	↑ expression of the M2 phenotype marker CD206 ↑ phagocytic capacity of macrophages ↑ protection in lung injury ↓ production of cytokines (TNF-α and IL-8)	↓ OXPHOS

ADSCS: adipose derived stem cells, anti-ox: anti-oxidant, ARDS: acute respiratory distress syndrome, BM-MSC: bone marrow MSC, CAT: catalase, DIC: disseminated intravascular coagulation, EV: extracellular vesicles, GPX: glutathione peroxidase, GSH: reduced glutathione, HI: hypoxia-ischemia, HypEV: EV release by cells under hypoxia, IC: intracavernous, IFN: interferon, IL: interleukin, IP: intraperitoneal, IRI: ischemia-reperfusion injury, IV: intravenous, LC3: microtubule-associated protein light chain 3, MDA: malondialdehyde, MDMs: monocyte derived macrophages, Mfn: mitofusin, mito: mithcondria, M2 phenotype: alternatively activated macrophages, MMP: mitochondrial membrane potential, MNP: microneedle patch, MSC: mesenchymal stromal cells, MV: microvesicles, NRF2: nuclear factor erythroid 2-related factor 2, OCR: oxygen consumption rate, OXPHOS: oxidative phosphorylation, PGC1-α: Pparg coactivator 1-alpha, PRDX: peroxiredoxin, ROS: reactive oxygen species, SOD: superoxide dismutase, TFAM: mitochondrial transcription factor A, TNFα: tumor necrosis factor alpha, UC-MSC: umbilical cord MSC, ↑: increase/ improve, ↓: decrease, ≈: data have been estimated from the graphs.