Table 1.

Studies employing exosomes with or without modification for treatment of cardiovascular disease (CVD). Up- or down-regulation of target molecules is symbolized by red or blue arrows respectively.

EV Sources	Therapeutic Agents	Target Molecules		Mode of Action	Species/Diseases Conditions	References
Exosomes from cardiac fibroblast-derived induced pluripotent stem cells (iPS cells)	miR-21-5p miR-210-3p		ROS FLASH Casp8ap2	Anti-apoptotic Cell survival	Mouse/ Myocardial Ischemia and Reperfusion	[110]
Exosomes from cardiomyocytes	miR-222 miR-143		CD31+ cells	Improved neovascularizatio n	Mouse/Acute Myocardial Infarction	[122]
Exosomes from cardiac progenitor cells	miR-210   miR-132		Ephrin PTP1b RasGAP-p120	Anti-apoptotic Cell survival Enhance endothelial tube formation	Mouse/Myocardial Infarction	[111]
Exosomes from hypoxic rat cardiomyoblasts	miR-21-5p miR-378-3p   miR-152-3p let-7i-5p		PTEN PDCD4 Atg12 Faslg Bcl-2	Anti-apoptotic Cell survival	Acute Myocardial Infarction	[114]
Exosomes from human pericardial fluid	miR-let-7b-5p		TGFBR1	Vascular remodeling Pro-angiogenic	Mouse/Limb Ischemia	[90]
Exosomes from human pericardial fluid	Clusterin		EMT genes	Epicardial Activation Arteriogenesis Anti-apoptotic	Mouse/Acute Myocardial Infarction	[123]
Exosomes from CD34+ stem cells	miR-126-3p Shh		SPRED1 PTCH1GLI TFs	Vascular remodeling Pro-angiogenic	Mouse/Myocardial Ischemia	[113] [124]
Exosomes from rat plasma	HSP70		TLR4 ERK1/2 p38MAPK	Anti-apoptotic	Rat/Ischemic-Reperfusion Injury	[125]
AAV-mediated Gene therapy	SERCA2a		Intracellular Ca2+	Enhanced cardiomyocyte contractility	Mouse/Chronic Heart Failure	[9,126]
Exosomes from CXCR4- overexpressing lentiviral transduced MSC	CXCR4		IGF-1α pAk TCaspase 3	Cardiac remodeling Pro-angiogenic	Rat/Myocardial Infarction	[115]
Exosomes from Akt-overexpressing adenoviral transduced MSC	Akt		PDGF-D	Vascular endothelial formation Pro-angiogenic	Rat/Acute Myocardial Infarction	[116]
Exosomes from HIF-1α -overexpressing lentiviral transduced MSC	HIF-1α		Jagged1 Notch target genes	Endothelial formation Pro-angiogenic	Mouse/Myocardial Ischemia	[117]
Curcumin in exosomes from EL-4 cells	Curcumin (a bioactive compound)		TGFβ1 MMP-1, -9	Inhibits myofibroblast differentiation Promote collagen degradation	Mouse/Septic Shock	[127,128]

Note: This table focuses on key miRNAs and proteins with therapeutic potential to treat CVD. Existing literature shows miRNAs to be one of the key functional content of EVs. However, EVs are shown to contain many other RNA species, including protein-coding mRNAs (or their fragments), mtRNAs (mitochondrial RNA), snoRNA (small nucleolar RNA), yRNA, piRNA (piwi-interacting RNA), lncRNA (long non-coding RNA) and vRNA (vault RNA), and a diverse array of proteins that could drive phenotypic differences [129,130]. For instance, Lopatina et al. showed that EVs secreted by platelet-derived growth factors can protect tissue from ischemic injury by transporting and inducing the expression of lncRNA MALAT1 (Metastasis Associated Lung Adenocarcinoma Transcript 1), a well-known pro-angiogenic and anti-inflammatory regulator [131].