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Ischemic stroke therapy consists of acute phase and preventive treatment strategies. Acute-phase ischemic stroke treatment includes systemic thrombolysis (rt-PA) and mechanical thrombectomy (endovascular therapy). Rt-PA is a very potent thrombolytic agent but its effectiveness is time-dependent. For the prevention of stroke recurrence (secondary stroke prevention) according to the TOAST classification, antiplatelet therapy (aspirin, clopidogrel, and cilostazol) is used for atherothrombotic and lacuna strokes, while anti-coagulant therapy (warfarin and direct oral anticoagulants [DOACs]) are used for cardiogenic cerebral embolism. Additionally, neuroprotective therapy using edaravone, a free radical scavenger, has recently been introduced to minimize brain tissue damage. Recently, neuronal regenerative therapies using stem cells have also been developed.

Increase in vascular permeability of the blood-brain barrier (BBB) is a distinct pathology following ischemic stroke. In previous studies, we demonstrated that liposomal drug delivery system (DDS)-based delivery of neuroprotectants is useful for treating cerebral ischemia/reperfusion injury. Additionally, our previous studies reported that combination therapy with liposomal fasudil plus tissue plasminogen activator (t-PA), a thrombolytic agent, brings about decrease in the risk of t-PA-derived cerebral hemorrhage and prolong the therapeutic time window of t-PA for treating acute ischemic stroke. However, accumulation of systemically administered liposomes into the brain parenchyma is still limited, and new technologies are needed that can overcome the BBB. The unique properties of leukocytes and exosomes, one of the extracellular vesicles, make them promising candidates for overcoming biological barriers (including the BBB) for drug delivery, as leukocytes and certain exosomes were reported to be able to permeate through the inflamed BBB in the ischemic stroke area. We prepared leukocyte-mimetic liposomes (LM-Lipo) via transfer of leukocyte membrane proteins by employing a phenomenon called intermembrane protein transfer, and demonstrated that LM-Lipo could pass through the layer of inflamed endothelial cells via regulation of intercellular junctions, like leukocytes. Additionally, we showed that LM-Lipo efficiently penetrated into spheroids of cancer cells, and inhibited their growth by entrapped doxorubicin. Taken together, it was suggested that imparting leukocyte-like characteristics to liposomes may be an effective approach to overcoming biological barriers. Herein, we summarize our findings regarding liposomal DDS for ischemic stroke therapy and recent approaches to develop biomembrane-mimetic DDS using leukocytes and exosomes.