Table 1.

Recent studies highlighting delivery modalities of cardiac regenerative EV therapies

Mode of EV Delivery	Study Description	Disease Model	EV Source	Key Findings	Ref.
Intravenous	Intravenous delivery of engineered EVs for targeted treatment of injured myocardium	Mouse model of MI	MSC EVs, cells transfected to express ischemic myocardium-targeting peptide on EV membrane	Enhanced homing of modified EVs to injured myocardium. Engineered EVs reduced inflammation, increased M2 macrophage polarization, increased angiogenesis, reduced infarct size, and preserved cardiac function compared to native EV infusions and controls.	[126]
Intracoronary, Intramyocardial	Comparison of intracoronary infusion versus intramyocardial injection of EVs to treat MI	Porcine model of MI	Cardiosphere-derived cell (CDC) EVs	Higher uptake and retention of EVs after intramyocardial injection compared to intracoronary infusion. Intramyocardial delivery exhibited decreased infarct size, decreased apoptosis, and increased functional rescue compared to intracoronary delivery and controls.	[148]
Intramyocardial	Intramyocardial injection of preconditioned EVs to treat MI	Mouse model of MI	CM EVs, post-hypoxic and ischemic preconditioning	Preconditioning upregulated angiogenic miR-143 and miR-222 in EVs. EVs promoted angiogenesis, improved survival, and increased ejection fraction post-MI.	[60]
Cardiac Patch	Surgical implantation of collagen-gelfoam cardiac patch for slow-release of encapsulated iPSC or CM EVs to treat MI	Rat model of MI	iPSC EVs versus CM EVs	Sustained local release of encapsulated EVs observed over 7 days. CM EV patches reduced hypertrophy, arrythmias, apoptosis, and infarct size, while increasing ejection fraction 4 weeks after implantation compared to iPSC EV patches and controls.	[12]
Stent Coating	Designing EV-eluting stent (EES) coatings for the prevention of re-stenosis and late stent thrombosis post-stenting	Rat models of renal ischemia-reperfusion injury and hindlimb ischemia	MSC EVs	EVs were successfully conjugated to stent coatings, exhibiting extended local release and uptake. EES reduced smooth muscle cell migration and re-stenosis compared to bare metal stents. EES exhibited enhanced re-endothelialization compared to conventional drug-eluting stents.	[149]
Inhalation, Oral, Intraperitoneal, Intravenous	Development of inhaled cardiac-targeting nanoparticles for delivery of regenerative biomolecules to the heart	Mouse model of diabetic cardiomyopathy, healthy rats and pigs	Synthetic calcium phosphate (CaP) nanoparticles, loaded with peptide or miRNA	Inhalation resulted in the most targeted and efficient delivery of CaP to the heart compared to oral, intraperitoneal, and intravenous methods. Inhaled peptide-loaded CaP led to complete cardiac functional recovery in mice with diabetic cardiomyopathy and did not cause significant toxicity or cardiac side effects in rats or pigs.	[150,151]