Atherosclerotic plaques develop within the arterial intima, where rapid blood flow and high shear stress pose significant barriers to the adhesion of drug carriers to endothelial cells and their accumulation within plaques. To overcome these challenges, we developed a genetically engineered anaerobic bacterium, Shewanella oneidensis MR-1, harboring a plasmid encoding hirudin—a potent thrombin inhibitor—and green fluorescent protein (GFP). Notably, this system retains the intrinsic hypoxia-targeting capability of Shewanella oneidensis MR-1 and is designed to selectively release hirudin-loaded vesicles in response to the acidic microenvironment within plaques. These bioengineered vesicles enable site-specific drug release, promoting localized accumulation at the lesion. The released hirudin effectively dissolves thrombi embedded within vulnerable plaques and modulates foam cell metabolism, thereby attenuating plaque progression. Our results demonstrate that the SO@AHG system offers a novel and precise therapeutic strategy for atherosclerosis, and highlights the potential of bacteria-mediated targeted delivery for cardiovascular disease treatment.