Thrombolytic drugs for ischemic stroke: historical perspective, state of play, and future developments.

Thrombolytic agents are serine proteases or related enzymes that facilitate blood clot breakdown via a process called thrombolysis. They work either indirectly, via activation of plasminogen into plasmin-a potent fibrin-degrading enzyme-or by direct dissolution of fibrin within clots. Numerous clinical trials investigating thrombolytic candidates for major thrombotic conditions, such as heart attack and acute ischaemic stroke (AIS), have led to the development of several potential therapies. However, while some drugs show clinical benefits, most still possess substantial limitations, especially for the treatment of AIS. Recombinant tissue-type plasminogen activator (rt-PA; alteplase) was the only clot-busting medication officially approved by the Food and Drug Administration for AIS from 1996 until 2024, until the recent approval of its mutated version, tenecteplase (2025). However, the use of rt-PA is significantly limited by its short plasma half-life, and both rt-PA and tenecteplase possess reduced efficacy against platelet-rich thrombi and a narrow, guideline-recommended therapeutic window up to 4.5 hours from stroke onset, primarily due to a diminished risk-benefit profile beyond this time point. While recent thrombectomy techniques offer ground-breaking ways for the removal of large clots, a pressing need remains to improve pharmacological thrombolysis. Novel strategies, including the fusion of clot-busting enzymes with thrombus-targeting antibodies and nanotechnology-based delivery systems, are being tested for their ability to increase the precision and safety of thrombolytic therapy. This review will articulate the historical milestones in thrombolysis, discuss key thrombolytic agents and their generational derivatives, and explore innovative approaches to advance this life-saving therapy for AIS.