Artificial apoptotic cells/VEGF-loaded injectable hydrogel united with immunomodification and revascularization functions to reduce cardiac remodeling after myocardial infarction

Abstract Currently, single therapeutic strategy designed for only boosting anti-inflammatory response or angiogenesis in treating myocardial infarction (MI) has met with limited success due to complicated pathological mechanism. Herein, we propose to create artificial apoptotic cells (AACs) by customizing liposomes with phosphatidylserine (PS) exposing at outlayer, in mimicking the function of apoptotic cells, with an aim to promote M2 polarization of macrophages. The AACs and vascular endothelial growth factor (VEGF) are encapsulated into an extracellular matrix-mimetic injectable hydrogel that recapitulates sulfated glycosaminoglycan. The loaded AACs and VEGF can realize earlier quick and slowly sustainable release, respectively, which is governed by distinct electrostatic interactions. The controlled spatio-temporal delivery of AACs and VEGF achieves on-demand regulation of inflammation immune response and enhanced angiogenesis. In the rat model of MI with intramyocardial administration of this injectable hydrogel bearing AACs and VEGF, the local precise release of AACs inhibits the inflammatory response and reduces the apoptosis of cardiomyocytes. Meanwhile, the sustainable release of VEGF activates the VEGF signaling pathway and thus facilitates revascularization in the targeted infarcted region, eventually contributing to a significant improvement in cardiac function and alleviating pathological remodeling of the left ventricle.