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Atherosclerosis (AS) is a chronic inflammatory disease that primarily affects large and medium-sized arteries and serves as the major pathological basis for cardiovascular diseases such as coronary heart disease. During the progression of AS, macrophages play a crucial role in promoting inflammatory regulation. Sustained local inflammatory responses are triggered by the accumulation of macrophages in arterial walls, which either promote or inhibit the development of AS by modulating inflammatory progression, plaque stability, and the surrounding immune microenvironment. Therefore, therapeutic strategies targeting macrophages and eliminating pro-inflammatory features in the plaque microenvironment hold promise as novel approaches to slow the progression of AS. With the deepening understanding of the mechanisms underlying AS, numerous innovative nanotherapeutic systems for its diagnosis and treatment have been developed. Here, we review strategies for designing novel nanosystems to treat AS, including modifying targeting ligands and utilizing biomimetic nanoparticles to enhance drug accumulation in target lesions and improve bioavailability. Macrophage-targeted nanotherapeutic approaches aim to reduce plaque burden and inflammation by regulating macrophage apoptosis, autophagy, and inducing efferocytosis synergistically. Concurrently, the development of intelligent responsive nanoparticles based on the inflammatory microenvironment enables targeted elimination of inflammatory characteristics within plaque microenvironments. These strategies demonstrate significant potential for application in AS treatment.