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, Wen Zeng
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. 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.