Therapeutic Suppression\nof Atherosclerotic Burden\nand Vulnerability via <i>Dll4</i> Inhibition in Plaque Macrophages\nUsing Dual-Targeted Liposomes

Atherosclerosis, characterized by chronic inflammation\nwithin the\narterial wall, remains a pivotal concern in cardiovascular health.\nWe developed a dual-targeted liposomal system encapsulating Dll4-targeting\nsiRNA, designed to selectively bind to pro-inflammatory M1 macrophages\nthrough surface conjugation with anti-F4/80 and anti-CD68 antibodies.\nThe Dll4-targeting siRNA is then delivered to the macrophages, where\nit silences Dll4 expression, inhibiting Notch signaling and reducing\nplaque vulnerability. Emphasizing accuracy in targeting, the system\ndemonstrates effective suppression of Dll4, a key modulator of atherosclerotic\nprogression, and vulnerability via VSMCs phenotypic conversion and\nsenescence. By employing liposomes for siRNA delivery, we observed\nenhanced stability and specificity of the siRNA. Alongside the therapeutic\nefficacy, our study also evaluated the safety profile and pharmacokinetics\nof the dual-targeted liposomal system, revealing favorable outcomes\nwith minimal off-target effects and optimal biodistribution. The integration\nof RNA interference techniques with advanced nanotechnological methodologies\nsignifies the importance of targeted delivery in this therapeutic\napproach. Preliminary findings suggest a potential attenuation in\nplaque development and vulnerability, indicating the therapeutic promise\nof this approach. This research emphasizes the potential of nanocarrier-mediated\nprecision targeting combined with a reassuring safety and pharmacokinetic\nprofile for advancing atherosclerosis therapeutic strategies.