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

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. Dextran‐ and ischemic cardiac homing peptide‐conjugated apoptotic cell‐derived nanovesicles (ApoNV‐DCs) actively target infarcted myocardium and are selectively phagocytosed by macrophages in infarcted heart. ApoNV‐DCs polarize macrophages M1 to M2 phenotype and decrease inflammatory responses. Immunomodulation by ApoNV‐DCs not only reduce cardiac adverse remodeling but also prevent cardiac function aggravation after myocardial ischemia‐reperfusion injury.