AIEgen-Based Biomimetic Nanoplatform for Targeted Synergistic Sonodynamic Therapy and Macrophage Reprogramming of...

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.