**1. Introduction**

Stroke is an unexpected and acute brain disease. It is reported that one of nineteen deaths is related to stroke in the United States, and the mortality rate of stroke is as high as 30% [1]. Stroke is defined by a condition caused by a hemorrhage or occlusion of cerebral blood vessels. Lacking of blood flow in the brain causes dysfunctions of brain cells, oxidative stress, and neurological damage [2]. The symptoms of stroke include numbness, confusion, and aphasia, and those signs are related to injured areas in the brain [3]. Since 87% of strokes are related to ischemia in the brain and 13% are involved with the hemorrhage, this review will focus on discussing how nanotechnology improves therapies and diagnosis of ischemia stroke.

Cerebral ischemia initiates a cascade of pathological processes, eventually causing neuron death. Reperfusion is a clinical method to restore the blood flow in the brain by administration of tissue plasminogen activator (t-PA) or mechanical thrombectomy (MT) for treatment of ischemic stroke [4]. However, reperfusion often leads to tissue damage because oxygen influx of reperfusion generates reactive oxygen species (ROS), initiating inflammatory responses including cytokine production and leukocyte infiltration [5]. Many neuroprotectants have been developed to alleviate reperfusion-induced injury, but none of them were clinically approved. There are several reasons for this failure: (1) ineffective drug delivery into the brain because of blood brain barrier (BBB), (2) drugs with short circulation times, poor stability, and toxicity, (3) difficulty in choosing right drugs and doses due to the heterogenicity of stroke (e.g., disease locations and severity).

Recently, nanotechnology emerges as innovative tools in drug delivery and diagnosis to treat a wide range of diseases, such as cancer and inflammatory disorders [6–13]. In the case of ischemic stroke, nanoparticles could possibly deliver therapeutics across BBB, prolong the drug circulation, and increase the drug accumulation at diseased sites. In addition, nanoparticles can be utilized as innovative diagnostic systems to detect several biomarkers (such as ROS and neurotransmitters) in the brain

for early-stage stroke diagnosis. In this review, we firstly describe the physiopathology of ischemic stroke and current limitations in therapy and diagnosis. Then, we discuss how nanotechnology offers opportunities in treating ischemic stroke, highlighting the recent progress on delivering neuroprotective agents, anti-inflammatory drugs, and small interfering RNA (siRNA) to alleviate ischemic injuries. We also review the applications of nanomaterials in stroke diagnosis. Finally, we describe new opportunities in translating nanoparticle-based therapies to clinic in the prevention and treatment of ischemic stroke.

#### **2. Pathology of Stroke and Current Therapies**

#### *2.1. Molecular Mechanisms for Pathology in Stroke*

Acute ischemic stroke and subsequent reperfusion cause a series of pathophysiological changes including neuronal damage, oxidative stress, local inflammation, and loss of blood brain barrier (BBB) integrity [14]. The cellular process and mechanism of ischemic stroke and the ischemic injury cascade is summarized in Figure 1. Herein, we mainly discuss neuronal damage, oxidative stress, and inflammation responses that contribute to the pathogenesis of ischemic stroke. These three events are intertwined, and each can result in brain damage.

**Figure 1.** The cellular process and mechanism of ischemic stroke and the ischemic injury cascade.

#### 2.1.1. Neuronal Damage

Neurons are the major components in brain and are particularly vulnerable to ischemia. Studies have shown that acute cerebral ischemia causes the vasculature infarction, thus leading to neuronal death in rodent models [15]. Due to reduced blood supply in the ischemic brain, adenosine triphosphate (ATP) level drops and lactate acidosis leads to the loss of ionic homeostasis in neurons [14]. Failure to maintain the ion gradients results in depolarization of cell membranes and therefore activating a variety of ion channels such as calcium and sodium channels. Those events also cause the excessive release of glutamate, which initiate more loss of neuronal cells [16]. Glutamate is a major excitatory neurotransmitter in nervous system regulating a variety of excitatory synapses, but high levels of extracellular glutamate can induce the cell death in the late stage. Dead neural cells release damage-associated molecular patterns (DAMPs), which activate the innate and adaptive immune system, initiating inflammatory pathways [17].
