Fibrin-targeted ROS-scavenging micelles with photothermal and NO delivery for thrombolysis and post-thrombotic vascular remodeling

Cardiovascular diseases (CVDs), a major contributor to global mortality, are often precipitated by thrombosis. Conventional antithrombotic therapies based on thrombolytic medicine often yield suboptimal therapeutic outcomes and are often accompanied with the risk of tissue bleeding. Despite of advances in nanocarrier-mediated drug delivery with improved hemostatic safety and thrombolytic efficiency, the integration of thrombus targeting, reactive oxygen species (ROS) scavenging, thrombolysis, and post-treatment vascular repair to achieve comprehensive thrombus eradication while preventing recurrence remains a challenge. Herein, we develop pentapeptide CREKA-terminated poly(ethylene glycol)-block-poly(propylene sulfide) (CREKA-PEG-b-PPS) micelles with ROS-scavenging properties to load indocyanine green (ICG) and the NO donor, N,N′-di-sec-butyl-N,N′-dinitroso-1,4-phenylenediamine (BNN6). Fibrin-targeting peptide CREKA enables precise targeting thrombotic sites after intravenous injection. The thioether moieties in the PPS block scavenge ROS, thereby effectively alleviating the oxidative stress microenvironment at thrombus sites. Upon exposure to light irradiation at 808 nm, photothermal effects from ICG can facilitate the deep thrombus penetration and thrombolysis effect, further triggering the localized release of NO from BNN6. Moreover, NO contributes to the restoration of endothelial cell function, thereby maintaining vascular homeostasis post-thrombolysis. Integration of ROS-scavenging, localized photothermal effects, and NO release achieves rapid clot ablation, restoring complete blood flow in a murine carotid artery thrombosis model while promoting vascular repair and homeostasis. Thus, the developed micelles represent a safe and efficient therapeutic strategy for the treatment of thrombosis.