A Dual‐Phase Exosomal Nanotherapy Enhances Continual Efferocytosis by Coordinating Checkpoint Inhibition and Metabolic Reprogramming in Atherosclerosis

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ABSTRACT Atherosclerosis is a chronic inflammatory disease characterized by defective efferocytosis, which contributes to necrotic core expansion and plaque instability. This dysfunction arises from two key barriers: first, impaired recognition of apoptotic cells due to activation of the CD47–SIRPα immune checkpoint; and second, insufficient metabolic processing of apoptotic cell‐derived substrates, which limits the capacity for continual efferocytosis. Arg1‐mediated arginine metabolism has emerged as a crucial pathway supporting this process. To address these limitations, we created Am@SExo, a dual‐functional engineered exosome derived from macrophages that unites checkpoint inhibition with metabolic reprogramming. The vesicles overexpress SIRPα on its surface to competitively engage CD47 on apoptotic cells and relieve the inhibitory signal, facilitating initial binding and uptake. Subsequently, it delivers Arg1 mRNA to recipient macrophages, driving an arginine to putrescine program aligned with Rac1 and actin remodeling to sustain successive rounds of clearance. In ApoE −/− mice, systemic administration of Am@SExo significantly reduced necrotic core area, increased fibrous cap thickness, and enhanced features of plaque stability. Together, our findings demonstrate that Am@SExo as a single‐platform, dual‐phase modulator that restores macrophage continual efferocytosis, offering a promising strategy to resolve inflammation and stabilize atherosclerotic plaques.

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