Ultrasound-responsive theranostic platform for the timely monitoring and efficient thrombolysis in thrombi of tPA resistance

• Published in: Nature communications Vol. 15; no. 1; pp. 6610 - 17
• Main Authors: Lin, Lin, Ba, Zhaojing, Tian, Hao, Qin, Haoxiang, Chen, Xi, Zhou, Xin, Zhao, Shanlan, Li, Lang, Xue, Fangchao, Li, Hong, He, Lang, Li, Xiaochen, Du, Jiahui, Zhou, Zhenhua, Zeng, Wen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/107; 14/19; 38/91; 631/1647/350/354; 631/61/350/354; 64/86; 692/699/75/593/567; Animals; Bonded joints; Cardiovascular system; Disease Models, Animal; Drug Resistance; Extracellular Traps - metabolism; Fibrin; Fibrin - metabolism; Fibrinolytic Agents - pharmacology; Fibrinolytic Agents - therapeutic use; Humanities and Social Sciences; Humans; Leukocytes (neutrophilic); Lysine; Male; Monitoring; multidisciplinary; Occlusion; Rats; Rats, Sprague-Dawley; Real time; Science; Science (multidisciplinary); Stroke - diagnostic imaging; Stroke - drug therapy; Stroke - therapy; Swine; t-Plasminogen activator; Theranostic Nanomedicine - methods; Thromboembolism; Thrombolysis; Thrombolytic Therapy - methods; Thrombosis; Thrombosis - diagnostic imaging; Thrombosis - drug therapy; Tissue engineering; Tissue Plasminogen Activator - therapeutic use; Ultrasonic imaging; Ultrasound
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50741-y

There is no effective and noninvasive solution for thrombolysis because the mechanism by which certain thrombi become tissue plasminogen activator (tPA)-resistant remains obscure. Endovascular thrombectomy is the last option for these tPA-resistant thrombi, thus a new noninvasive strategy is urgently needed. Through an examination of thrombi retrieved from stroke patients, we found that neutrophil extracellular traps (NETs), ε-(γ-glutamyl) lysine isopeptide bonds and fibrin scaffolds jointly comprise the key chain in tPA resistance. A theranostic platform is designed to combine sonodynamic and mechanical thrombolysis under the guidance of ultrasonic imaging. Breakdown of the key chain leads to a recanalization rate of more than 90% in male rat tPA-resistant occlusion model. Vascular reconstruction is observed one month after recanalization, during which there was no thrombosis recurrence. The system also demonstrates noninvasive theranostic capabilities in managing pigs’ long thrombi (>8 mm) and in revascularizing thrombosis-susceptible tissue-engineered vascular grafts, indicating its potential for clinical application. Overall, this noninvasive theranostic platform provides a new strategy for treating tPA-resistant thrombi. There is no noninvasive solution for tPAresistant thrombi as the mechanism remains obscure. Here, the authors show a constructed ultrasound-responsive theranostic platform for real-time monitoring and efficient thrombolysis by breaking the keychain in tPA-resistant thrombi.