Multitargeted Immunomodulatory Therapy for Viral Myocarditis by Engineered Extracellular Vesicles

Area of Science:

• Cardiovascular Research
• Immunology
• Biomedical Engineering

Background:

• Viral myocarditis (VM) is driven by classically activated M1 macrophages.
• M2 macrophage-derived extracellular vesicles (M2 EVs) show immunomodulatory potential but lack in vivo targeting.
• Effective delivery of M2 EVs to cardiac tissue is crucial for therapeutic efficacy.

Purpose of the Study:

• To engineer M2 EVs with enhanced cardiac targeting for VM treatment.
• To investigate the therapeutic efficacy of engineered M2 EVs in a mouse model of VM.
• To elucidate the mechanism of M2 EV-mediated macrophage reprogramming in the cardiac immune microenvironment.

Main Methods:

• Development of cardiac-targeting peptide (CTP) and platelet membrane (PM)-engineered M2 EVs enriched with viral macrophage inflammatory protein-II (vMIP-II), termed CTP/PM-M2 EVs^{vMIP-II-Lamp2b}.
• Intravenous injection of engineered M2 EVs into a mouse model of VM.
• Assessment of EV biodistribution, cellular uptake, macrophage reprogramming, and cardiac repair.

Main Results:

• CTP/PM-M2 EVs^{vMIP-II-Lamp2b} demonstrated enhanced targeting and accumulation in the myocardium.
• Engineered EVs were efficiently endocytosed by macrophages in the cardiac inflammatory microenvironment.
• Successful reprogramming of M1 macrophages to M2 macrophages, leading to reduced inflammation and cardiac repair.
• vMIP-II enhanced EV targeting and collaborated with M2 EVs to regulate macrophage phenotype and chemokine receptor levels.

Conclusions:

• CTP-and-PM-engineered M2 EVs^{vMIP-II-Lamp2b} represent a promising therapeutic strategy for viral myocarditis.
• This approach enhances EV delivery to cardiac tissue and facilitates macrophage reprogramming.
• The engineered EVs show potential for clinical application in treating VM and promoting cardiac healing.