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

Lin Lin, Zhaojing Ba, Hao Tian, Haoxiang Qin, Xi Chen, Xin Zhou, Shanlan Zhao, Lang Li, Fangchao Xue, Hong Li, Lang He, Xiaochen Li, Jiahui Du, Zhenhua Zhou () and Wen Zeng ()
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Lin Lin: Third Military Medical University
Zhaojing Ba: Third Military Medical University
Hao Tian: Third Military Medical University
Haoxiang Qin: Third Military Medical University
Xi Chen: Third Military Medical University
Xin Zhou: Third Military Medical University
Shanlan Zhao: Third Military Medical University
Lang Li: Third Military Medical University
Fangchao Xue: Third Military Medical University
Hong Li: Third Military Medical University
Lang He: Third Military Medical University
Xiaochen Li: Third Military Medical University
Jiahui Du: Third Military Medical University
Zhenhua Zhou: Third Military Medical University
Wen Zeng: Third Military Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-50741-y

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