Abstract / Summary
Abstract The efficacy of thrombolysis in acute ischemic stroke with large vessel occlusion (AIS-LVO) is frequently limited by thrombolytic resistance and bleeding risk. The synergy of tenecteplase (TNK) and deoxyribonuclease-I (DNase-I), however, is difficult to translate clinically: DNase-I has a short circulating half-life and low bioavailability and lacks thrombus-targeting capability even when stabilized, while TNK's lack of specificity predisposes to systemic hemorrhage—so a platform that stably, specifically, and synergistically delivers both agents to the thrombus is urgently needed. We therefore engineered a biomimetic nanosystem (TNK-DNaseI@ZPM), co-encapsulating TNK and DNase-I within a platelet membrane-cloaked zeolitic imidazolate framework-8 (ZIF-8) core for precise thrombus targeting and pH-responsive drug release. DNase-I degrades the neutrophil extracellular traps (NETs) scaffold around fibrin, sensitizing thrombi to TNK-driven fibrinolysis. This nanoformulation achieved rapid and superior recanalization while significantly reducing hemorrhagic risk, offering a biomimetic platform to overcome thrombolytic resistance and enable safer, more effective AIS-LVO recanalization.