Decursin‐Loaded Nanovesicles Target Macrophages Driven by the Pathological Process of Atherosclerosis

Abstract Atherosclerosis (AS) is a major pathological factor contributing to the mortality associated with ischemic heart disease and is driven primarily by macrophage‐mediated lipid accumulation and inflammatory processes. Conventional cardiovascular pharmacotherapies address these pathological mechanisms but often show limited efficacy, highlighting the need for innovative agents capable of effectively reducing lipid accumulation and inflammation with minimal toxicity. In this study, decursin, a monomer derived from traditional Chinese medicine, is shown to inhibit both lipid accumulation and inflammatory responses in macrophages through direct interaction with protein kinase Cδ (PKCδ), resulting in low cytotoxicity in vitro and negligible toxicity in vivo. To address the short half‐life of decursin, a targeted cascade drug delivery system (ALD@EM), which is specifically designed to target AS pathophysiology, is developed. This system employs ICAM‐1 and VCAM‐1 antibodies for plaque localization and incorporates low‐density lipoproteins (LDLs) to facilitate chemotaxis to lesion sites, with an inner layer of apoptotic endothelial cell membranes to increase macrophage internalization and drug release. As a result, ALD@EM nanovesicles significantly increased the accumulation and therapeutic efficacy of decursin within plaques, substantially reducing lipid deposition and plaque inflammation, thereby offering a novel strategy for targeted AS treatment.