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This invention discloses a sonodynamic synergistic thrombolysis system and its application. The system includes a tissue plasminogen activator variant, a sonosensitive agent, and an ultrasound source. The tissue plasminogen activator variant is an intravenously administered formulation, the sonosensitive agent is an intravenously infused formulation, and the ultrasound source is used to emit ultrasound during sonosensitive agent administration to activate the agent. This invention significantly improves thrombolysis efficiency and reduces thrombolytic agent dosage and bleeding risk through the dual synergistic effect of TNK-tPA enzymatic hydrolysis and sonodynamic chemical oxidation. The system can significantly improve vascular recanalization rate and blood flow velocity recovery rate, and has high biocompatibility. This invention is applicable to thrombolytic treatment of various thrombotic diseases and has the advantages of simple operation, strong targeting, and wide application range.