US-triggered on-demand NO-releasing biomimetic nanoparticle to Remodel endothelial microenvironment for enhancing atherosclerosis-specific gas therapy

Atherosclerosis (AS) is a chronic inflammatory disease driven by endothelial dysfunction, vascular smooth muscle cell proliferation, and insufficient resolution of inflammation. Nitric oxide (NO) plays a crucial role in vascular homeostasis by promoting endothelial cell proliferation, maintaining endothelial integrity, suppressing smooth muscle cell hyperplasia, and exerting potent anti-inflammatory effects. However, clinical application of NO is hindered by its short half-life, lack of targeting, and uncontrolled release. Here, we developed the biomimetic nanoparticles (B-NPs@MM) for targeted and controllable NO delivery by encapsulating the ultrasound (US)-responsive NO donor BNN6 into poly(lactic-co-glycolic acid) (PLGA) nanospheres followed by coating with macrophage-derived membranes. These biomimetic particles mimic natural macrophages to actively target inflamed atherosclerotic plaques and evade immune clearance. Upon localized US exposure, the system triggers rapid and on-demand NO release at the lesion site with spatiotemporal precision. <i>In vitro</i> and <i>in vivo</i> evaluations demonstrate effective NO delivery, enhanced endothelial repair, reduced inflammation, and inhibition of neointimal hyperplasia. This work presents a smart, remotely controlled NO nanotherapy platform based on artificial immune cell design, offering a promising strategy for precision treatment of AS.