Legumain‐Guided Ferulate‐Peptide Self‐Assembly Enhances Macrophage‐Endotheliocyte Partnership to Promote Therapeutic Angiogenesis After Myocardial Infarction

Abstract Promoting angiogenesis and modulating the inflammatory microenvironment are promising strategies for treating acute myocardial infarction (MI). Macrophages are crucial in regulating inflammation and influencing angiogenesis through interactions with endothelial cells. However, current therapies lack a comprehensive assessment of pathological and physiological subtleties, resulting in limited myocardial recovery. In this study, legumain‐guided ferulate‐peptide nanofibers (LFPN) are developed to facilitate the interaction between macrophages and endothelial cells in the MI lesion and modulate their functions. LFPN exhibits enhanced ferulic acid (FA) aggregation and release, promoting angiogenesis and alleviating inflammation. The multifunctional role of LFPN is validated in cells and an MI mouse model, where it modulated macrophage polarization, attenuated inflammatory responses, and induces endothelial cell neovascularization compare to FA alone. LFPN supports the preservation of border zone cardiomyocytes by regulating inflammatory infiltration in the ischemic core, leading to significant functional recovery of the left ventricle. These findings suggest that synergistic therapy exploiting multicellular interaction and enzyme guidance may enhance the clinical translation potential of smart‐responsive drug delivery systems to treat MI. This work emphasizes macrophage‐endothelial cell partnerships as a novel paradigm to enhance cell interactions, control inflammation, and promote therapeutic angiogenesis.