A spatiotemporal selective bioinspired hybrid system engineered for preventing post-thrombolysis recurrence by inhibiting the ferroptosis pathway and reprogramming macrophages.

Cardiovascular diseases induced by arterial thrombosis, such as myocardial infarction and ischemic stroke, have gradually emerged as critical threats to human life and health. Sequentially targeted delivery systems are highly desired to be developed to improve the delivery of thrombolytics and anti-inflammatory medications to the site of the thrombus, respectively, to pursue a maximized combinational effect. Herein, we developed a probiotic-platelet hybrid vesicle-targeted drug delivery system (Fer-1@PLevs-C&U) to achieve sequential anti-thrombolytic delivery against thrombus and prevent its recurrence. The hybrid vesicles (PLevs) were prepared by mixing platelet membrane with Lactobacillus plantarum-derived bacterial extracellular vesicles (Levs) and further decorated with DSPE-PEG2000-CREKA, achieving "point-to-point" multi-covalent targeting of thrombus components. After targeted localization to the arterial thrombotic site, Fer-1@PLevs-C&U gradually releases the thrombolytic drug urokinase-type plasminogen activator (UPA) and Ferroptosis inhibitor (Fer-1) to facilitate thrombus dissolution and regulate the inflammatory microenvironment. By enhancing the eNOS expression and reducing the secretion of inflammatory factors TNF-α and IL-6, Fer-1@PLevs-C&U significantly reduced the inflammatory microenvironment and inhibited recurrent thrombus. Therefore, Fer-1@PLevs-C&U constitutes a novel biomimetic drug delivery platform with promising therapeutic potential and practical applicability.