Intravenous administration of fibrinolytic drugs is the standard treatment of acute thrombotic diseases. However, current fibrinolytics exhibit limited clinical efficacy because of their short plasma half-lives and might trigger hemorrhagic transformations. Therefore, it is mandatory to develop innovative nanomedicine-based solutions for more efficient and safer thrombolysis with biocompatible and biodegradable thrombus-targeted nanocarrier. Herein, fucoidan-functionalized hydrogel polysaccharide submicroparticles with high biocompatibility are elaborated by the inverse miniemulsion/crosslinking method. They are loaded with the gold standard fibrinolytic – alteplase – to direct site-specific fibrinolysis due to nanomolar interactions between fucoidan and P-selectin overexpressed on activated platelets and endothelial cells in the thrombus area. The thrombus targeting properties of these particles are validated in a microfluidic assay containing recombinant P-selectin and activated platelets under arterial and venous blood shear rates as well as in vivo. The experiments on the murine model of acute thromboembolic ischemic stroke support this product's therapeutic efficacy, revealing a faster recanalization rate in the middle cerebral artery than with free alteplase, which reduces post-ischemic cerebral infarct lesions and blood-brain barrier permeability. Altogether, this proof-of-concept study demonstrates the potential of a biomaterial-based targeted nanomedicine for the precise treatment of acute thrombotic events, such as ischemic stroke.

静脉注射纤溶药物是急性血栓性疾病的标准治疗方法。然而，目前的纤溶药物由于其血浆半衰期短而表现出有限的临床疗效，并且可能引发出血性转化。因此，必须开发创新的基于纳米医学的解决方案，以使用生物相容性和可生物降解的血栓靶向纳米载体进行更有效和更安全的溶栓。在此，通过反相细乳液/交联方法制备了具有高生物相容性的岩藻依聚糖功能化水凝胶多糖亚微粒。由于岩藻依聚糖和磷之间的纳摩尔相互作用，它们装载有金标准纤溶酶——阿替普酶——以指导特定部位的纤溶-选择素在血栓区域的活化血小板和内皮细胞上过度表达。这些颗粒的血栓靶向特性在含有重组P-选择素和活化血小板的微流体测定中在动脉和静脉血液剪切速率以及体内得到了验证。急性血栓栓塞性缺血性脑卒中小鼠模型实验支持该产品的治疗效果，显示大脑中动脉的再通速度比游离阿替普酶更快，可降低缺血后脑梗塞病变和血脑屏障通透性。总而言之，这项概念验证研究证明了基于生物材料的靶向药物的潜力用于精确治疗急性血栓事件，如缺血性中风的纳米药物。