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. In vitro and in vivo 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.