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.