Rescuing ischemic stroke by biomimetic nanovesicles through accelerated thrombolysis and sequential ischemia-reperfusion protection

Rational design of nanomedicine to accelerate thrombolysis and sequentially avoid thrombolysis-mediated reperfusion injury is still a challenge. Here, we develop a biomimetic nanovesicle (tPA/MNP@PM, tMP) by simple encapsulating melanin nanoparticles (MNP) and tPA with a platelet membrane vesicle (PM), which integrates the thrombus targeting property of PM, the photothermal conversion performance and free radical scavenging property of natural melanin for cascaded ischemic stroke treatment. Benefiting from natural thrombus-targeted adhesion capability of PM, nanovesicles could efficiently target thrombus site. Then near-infrared (NIR) mediated photothermal of MNP could lead to rupture of nanovesicles, thus achieving precise release of tPA in thrombus. Interestingly, local hyperthermia also increases the activity of tPA for accelerating thrombolysis. Afterwards, site specific released MNP (4.5 nm) accompanied by hemoperfusion can cross the BBB and accumulate in cerebral ischemia site, scavenging various free radicals and suppressing inflammation- and immune response-induced injury to achieve neuroprotection after thrombolysis. In addition, the biomimetic nanovesicle could block tPA-induced brain hemorrhage after stroke to improve thrombolytic therapy. The evaluation in ischemic stroke mice confirmed that the simple-prepared nanomedicine with cascaded thrombus targeting, precise thrombolysis and ischemia-reperfusion protection properties can significantly enhance the treatment effect of ischemic stroke. STATEMENT OF SIGNIFICANCE: Ischemic stroke is recognized as a leading cause of death and disability in the world. Rational design of nanomedicine to accelerate thrombolysis and sequentially avoid thrombolysis-mediated reperfusion injury is still a challenge. Herein, a biomimetic nanovesicle (tMP) was developed for sequential ischemic stroke treatment. It could overcome the drawbacks of free tPA for safe thrombolysis: i) platelet membrane biomimetic coating significantly increases thrombus targeting; ii) NIR-mediated photothermal of natural melanin precise controlled release of tPA in thrombus in situ, and local hyperthermia also increases the thrombolytic activity of tPA. Notably, released melanin nanoparticles (4.5 nm) accompanied by hemoperfusion can across BBB and avoid ischemia-reperfusion injury through free radical scavenging and inflammation/immune response suppression.