Artificial Biomarker-based Feedback-regulated Personalized Precise Thrombolysis with Lower Hemorrhagic Risk

Intravenous thrombolysis possesses critical defects in efficiency and post-thrombolysis hemorrhage due to the current empirical body weight-based medication strategy. However, the inherent heterogeneity of thrombi, instead of body weight, endows thrombi different thrombolysis resistance and affect the thrombolytic outcome. The lack of methods for perceiving thrombolysis resistance has severely hindered the precise medication of vascular embolization. Here, we described the relationship between the thrombin heterogeneity in thrombi and the thrombolysis resistance of thrombi, and created an artificial biomarker-based nano-patrol system to perceive and report the thrombolysis resistance of thrombi taking advantage of the specific recognition and allosteric ability of aptamer-based DNA structure. The nano-patrols are able to accomplish thrombolysis resistance-matched personalized precise therapy through the NIR-â…¡ laser-regulated synergistic thrombolytic effect, according to the feedback signal from artificial biomarkers. This new strategy depicted enhanced thrombolytic efficiency than alteplase for rats, mini pigs and clinical thrombi, achieved recanalization in thrombotic model where alteplase encountered failure. Moreover, the nano-patrol system remarkably reduced the infarct volume and the hemorrhagic transformation risk (0.12-fold of alteplase) of cerebral thrombosis. This nano-patrol system developed new tool for the assessment of thrombolysis resistance and personalized precise thrombolysis with lower hemorrhagic risk.当前基于经验性体重的给药方案，使得静脉溶栓（intravenous thrombolysis）在疗效及溶栓后出血并发症方面存在显著缺陷。血栓（thrombus）的固有异质性而非体重，赋予不同血栓各异的溶栓抵抗性，并直接影响溶栓结局。目前缺乏检测溶栓抵抗性的有效方法，这严重阻碍了血管栓塞症的精准给药治疗。本研究阐明了血栓内凝血酶（thrombin）异质性与血栓溶栓抵抗性之间的关联，并基于适配体（aptamer）介导的DNA结构所具备的特异性识别与变构能力，构建了一套基于人工生物标志物的纳米巡诊系统，用于感知并报告血栓的溶栓抵抗性。该纳米巡诊系统可依据人工生物标志物反馈的信号，借助近红外二区（NIR-Ⅱ）激光调控的协同溶栓效应，实现与溶栓抵抗性匹配的个性化精准治疗。相较于阿替普酶（alteplase），该新型策略在大鼠、小型猪及临床血栓样本中展现出更优的溶栓效率，可在阿替普酶治疗失败的血栓模型中实现血管再通。此外，该纳米巡诊系统可显著降低脑血栓的梗死体积与出血转化风险，其出血转化风险仅为阿替普酶的0.12倍。该纳米巡诊系统为溶栓抵抗性评估以及低出血风险的个性化精准溶栓治疗提供了全新工具。