Targeted Delivery of Apoptotic Cell-Derived Nanovesicles prevents Cardiac Remodeling and Attenuates Cardiac Function Exacerbation

Abstract

The modulation of inflammatory responses plays an important role in the pathobiology of cardiac failure. In a natural healing process, the ingestion of apoptotic cells and their apoptotic bodies by macrophages in a focal lesion result in resolution of inflammation and regeneration. However, therapeutic strategies to enhance this natural healing process using apoptotic cell-derived biomaterials have not yet been established. In this study, apoptotic bodies-mimetic nanovesicles derived from apoptotic fibroblasts (ApoNVs) conjugated with dextran and ischemic cardiac homing peptide (CHP) (ApoNV-DCs) for ischemia-reperfusion (IR)-injured heart treatment are developed. Intravenously injected ApoNV-DCs actively targeted the ischemic myocardium via conjugation with CHP, and are selectively phagocytosed by macrophages in an infarcted myocardium via conjugation with dextran. ApoNV-DCs polarized macrophages from the M1 to M2 phenotype, resulting in the attenuation of inflammation. Four weeks after injection, ApoNV-DCs attenuated cardiac remodeling, preserved blood vessels, and prevented cardiac function exacerbation in IR-injured hearts. Taken together, the findings may open a new avenue for immunomodulation using targeted delivery of anti-inflammatory nanovesicles that can be universally applied for various inflammatory diseases.