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Homocysteine serves as an independent risk factor for atherosclerosis. Here, we developed a synergistic nanotherapeutic strategy for hyperhomocysteinemic atherosclerosis (HHcy\u2010AS) by simultaneously targeting foam cells and diseased macrophages. Specifically, an aggregation\u2010induced emission (AIE) sonosensitizer TTPY\u2010COOH was encapsulated into OPN antibody\u2010modified polymer nanoparticles to form TP\u2010Ab cores, which were then co\u2010loaded with dexamethasone into ROS\u2010responsive platelet membrane\u2010liposome hybrid vesicles, yielding the final nanodrug TP\u2010Ab\/Dex@PL. Following intravenous injection, this nanoplatform utilizes platelet membranes to precisely target atherosclerotic plaques, where it rapidly disassembles within the high ROS environments. The released TP\u2010Ab cores selectively deliver TTPY\u2010COOH to foam cells\n                    <jats:italic>via<\/jats:italic>\n                    specific antibody recognition, where subsequent ultrasound\u2010triggered sonodynamic therapy induces cellular apoptosis. Meanwhile, locally released dexamethasone exhibits a robust anti\u2010inflammatory effect and reprograms M1 macrophages into the M2 phenotype, enhancing their efferocytosis for apoptotic foam cells. In an HHcy\u2010AS mouse model, TP\u2010Ab\/Dex@PL treatment significantly reduced plaque burden and improved plaque stability. This multifunctional nanoplatform integrates sonodynamic therapy, anti\u2010inflammatory effects, and macrophage reprogramming, offering\u00a0potential\u00a0for the precise clinical treatment of atherosclerosis.\n                  <\/jats:p>","DOI":"10.1002\/smll.74733","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T09:18:15Z","timestamp":1785489495000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AIEgen\u2010Based Biomimetic Nanoplatform for Targeted Synergistic Sonodynamic Therapy and Macrophage Reprogramming of Hyperhomocysteinemic Atherosclerosis"],"prefix":"10.1002","author":[{"given":"Yue","family":"Jia","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences Ningxia Medical University  Yinchuan Ningxia China"},{"name":"NHC Key Laboratory of Metabolic Cardiovascular Diseases Research Ningxia Medical University  Yinchuan Ningxia 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