Atherosclerosis (AS) is a major pathological basis of cardiovascular and cerebrovascular events, and plaque stability is strongly influenced by the metabolic and immune states of macrophages. This study aimed to develop a macrophage-targeting MOF-Evo nanodelivery system for PCSK9 inhibition and to investigate whether the PCSK9–HDAC3–H3K27ac-associated metabolic reprogramming pathway contributes to macrophage reprogramming and AS plaque stabilization.