AIEgen‐Based Biomimetic Nanoplatform for Targeted Synergistic Sonodynamic Therapy and Macrophage Reprogramming of Hyperhomocysteinemic Atherosclerosis

The instability and subsequent rupture of atherosclerotic plaques are driven primarily by the progressive enlargement of the lipid-rich necrotic cores coupled with local macrophage dysfunction, which readily trigger life-threatening acute cardiovascular and cerebrovascular events. Homocysteine serves as an independent risk factor for atherosclerosis. Here, we developed a synergistic nanotherapeutic strategy for hyperhomocysteinemic atherosclerosis (HHcy-AS) by simultaneously targeting foam cells and diseased macrophages. Specifically, an aggregation-induced emission (AIE) sonosensitizer TTPY-COOH was encapsulated into OPN antibody-modified polymer nanoparticles to form TP-Ab cores, which were then co-loaded with dexamethasone into ROS-responsive platelet membrane-liposome hybrid vesicles, yielding the final nanodrug TP-Ab/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-Ab cores selectively deliver TTPY-COOH to foam cells via specific antibody recognition, where subsequent ultrasound-triggered sonodynamic therapy induces cellular apoptosis. Meanwhile, locally released dexamethasone exhibits a robust anti-inflammatory effect and reprograms M1 macrophages into the M2 phenotype, enhancing their efferocytosis for apoptotic foam cells. In an HHcy-AS mouse model, TP-Ab/Dex@PL treatment significantly reduced plaque burden and improved plaque stability. This multifunctional nanoplatform integrates sonodynamic therapy, anti-inflammatory effects, and macrophage reprogramming, offering potential for the precise clinical treatment of atherosclerosis.