Potential nanotherapeutic strategies for perioperative stroke

Abstract Aims Based on the complex pathological environment of perioperative stroke, the development of targeted therapeutic strategies is important to control the development of perioperative stroke. Discussions Recently, great progress has been made in nanotechnology, and nanodrug delivery systems have been developed for the treatment of ischemic stroke. Conclusion In this review, the pathological processes and mechanisms of ischemic stroke during perioperative stroke onset were systematically sorted. As a potential treatment strategy for perioperative stroke, the review also summarizes the multifunctional nanodelivery systems based on ischemic stroke, thus providing insight into the nanotherapeutic strategies for perioperative stroke.

strokes and simple stroke, nanotherapeutic strategies for simple stroke are also potential for the treatment of perioperative stroke. Therefore, the current nanotherapeutic strategies for simple stroke are summarized to provide insight into the nanotherapeutic strategies for perioperative stroke.

| DEFINITI ON AND CL A SS IFI C ATI ON OF PERIOPER ATIVE S TROKE
The World Health Organization (WHO) defines perioperative stroke as a focal or diffuse cerebral neurological deficit caused by intraoperative or postoperative cerebrovascular etiology, which can last up to 24 h or result in death within 24 h of occurrence. Based on perioperative stroke data, hemorrhagic strokes account for 1%-4% of strokes, and perioperative strokes are predominantly embolic. 11 The mechanism of embolism in perioperative stroke is not well understood and may be related to the following factors (Table 1).

| MORB IDIT Y AND MORTALIT Y
A recent retrospective analysis, including 370,000 perioperative stroke patients, found the incidence of ischemic stroke to be 0.7% after a partial colectomy, 0.2% after a total hip replacement (0.2%), and 0.6% after a pulmonary surgery, 2.2%-5.2% after neurosurgery, and up to 2%-10% after cardiac and microvascular surgery. 18 The risk of PAIS in the elderly population increases with age, 19 from 0.1%-0.2% under 65 years of age to 0.5% between 65 and 74 years of age, and 1.0% over 75 years of age. 20,21 Despite current improvements in surgical techniques and surgical treatments, the incidence of perioperative strokes has not decreased significantly, increasing to 0.8% in patients undergoing non-cardiac major vascular surgery.
The mortality rate of perioperative strokes is 18%-26% higher compared with non-operative stroke patients. 22

| RIS K FAC TOR S
Perioperative stroke is associated with multiple risk factors, as detailed in Table 2 4 | PATHOPHYS IOLOGY OF PERIOPER ATIVE S TROKE S Perioperative stroke is dominated by ischemia and embolism. In an ischemic stroke, vascular occlusion leads to the disorders of local blood supply in the corresponding brain regions, 33 which induces a complex series of cascade reactions at the (sub)cellular and molecular levels, 34,35 and ultimately leads to cellular and tissue damage. [36][37][38] The pathological biochemical reaction of an ischemic stroke begins with energy deprivation induced by a lack of oxygen and glucose supply to local brain tissue. 39,40 This is followed by stimulation of neuronal depolarization and glutamate release, causing calcium inward flow and elevated sodium ion content in the intracytoplasmic, and more glutamate release which leads to cellular excitotoxicity and cellular swelling, 41 ion channel dysfunction, and massive reactive oxygen and/or nitrogen species, ROS/RNS or RONS production. 42 These pathological and biochemical changes at the cellular and molecular levels further spread to neighboring cells, activating a series of enzymatic cascade reactions that eventually lead to the cell membrane and mitochondrial damage and production of RONS 43,44 ; the production of RONS can further damage mitochondria and DNA, eventually leading to cellular necrosis or apoptosis. [45][46][47][48] Inflammatory mediators or cytokines secreted by necrotic or apoptotic cells activate resting microglia in the brain and promote the invasion and infiltration of peripheral neutrophils and macrophages 49,50 ; activated microglia in the brain can further converge and aggregate toward damaged neurons, 51 mediating the release of pro-inflammatory factors, and start a vicious circle, aggravating neuronal damage. 52-55

| P OTENTIAL NANOTHER APEUTI C S TR ATEG IE S FOR PERI OPER ATIVE S TROKE
Nanotechnology is the science and technology of making substances from individual atoms and molecules, and it studies the properties and applications of materials with structural dimensions in the range of 1-100 nanometers. 56,57 Nanotechnology has developed rapidly in the last few decades and shows potential in the diagnosis and treatment of diseases. [58][59][60] The properties of nanomaterials differ significantly from those of equivalent materials at the corresponding macroscopic scales due to the different arrangement and spacing of surface atoms and molecules. 61 Nanomaterials have a great potential for biomarker development, disease diagnosis, and disease treatment, which are as follows: targeting damaged cells or tissues through molecular-scale interactions with improved and modified nanomaterials 62,63 ; controlled release of drugs by nano-engineered materials, [64][65][66] improving bioavailability, 67,68 transporting multiple drug formulations, and protecting drug compounds from degradation through different molecular modifications on the surface. 69 Nanomaterials are also a good alternative for developing drug strategies to penetrate the blood-brain barrier (BBB) by surface-functionalized ligand modifications that target and penetrate the BBB and increase its half-life in the blood circulation. 70,71 The passive/active targeting properties and improvement of the biostability of neurotherapeutic drugs increase the drug concentration in the pathological injury zone to achieve the desired therapeutic effect. [72][73][74] Nanotechnology provides a convenient platform for immobilizing and loading specific molecules or drugs on nanocarriers at higher loading rates. Nanomedicines also possess neuroprotective effects. [75][76][77] These properties of nanomaterials place them at the forefront of future precision diagnosis and treatment of central nervous system diseases, such as ischemic stroke. 78 Nanodrug delivery systems have unique advantages in the treatment of ischemic stroke, including enhanced BBB permeability, 79,80 targeting, and modulating drug release. 81 Most studies on nanotechnology-based therapies for ischemic stroke have focused on targeting revascularization, antioxidative stress, inflammation, and apoptosis, and promoting neuronal regeneration 82 as shown in Table 3.

| Nanodelivery strategies for revascularization
Currently, tissue plasminogen activator (tPA) intravenous thrombolysis remains the standard clinical treatment for patients with acute ischemic stroke within 4-5 h after the onset of ischemic stroke. 98,99 However, due to the limited "therapeutic window," only a minority of patients (<10%) receive this treatment. To broaden the therapeutic window of tPA, Mei et al. 83  To improve the thrombolytic effect, Wang et al. 85 designed a nanodelivery system based on gold@mesoporous silica core-shell nanospheres (Au@MSNs) (Figure 2A), which uses a near-infrared (NIR) laser (808 nm) to trigger the release of tPA. tPA is encapsulated with the phase change material 1-tetradecanol (Tet) into the pore of Au@MSNs. Laser irradiation is expected to release tPA from the nanocarrier when 1-tetradecanol is reconverted to liquid due to the photothermal conversion of gold ( Figure 2B). The photothermal-only treatment group also has a thrombolytic effect ( Figure 2C,D). The tPA-NPs achieved targeted release of tPA and enhanced the thermotherapeutic thrombolytic effect locally on NIR laser irradiation.
Further, ultrasound energy enhanced the efficacy of thrombolytic drugs. Daffertshofer et al. 100 showed that ultrasonic waves at 300-KHZ penetrated the bone efficiently and exposed the entire brain to ultrasound. However, there was a 36% hemorrhage rate in the group treated with rt-PA plus ultrasound. Focused ultrasound of the Willis circle, with or without microbubbles, appears to be a promising A larger phase III trial is currently being tested. 101 Tissue plasminogen activator activation of fibrinolytic is sys-

TA B L E 3 (Continued)
loaded with C5a aptamers (aC5a-FNA) ( Figure 3). After intrathecal injection, ac5A-FNA selectively alleviated C5A-mediated neurotoxicity and effectively relieved oxidative stress in the brain. Another study 91 also showed that ultra-small molybdenum polyoxomethoic acid nanoclusters (POM) had excellent ROS scavenging capability by changing their reduction and oxidation states. After intrathecal injection, POM nanoclusters were preferentially uptake by the brain, leading to rapid accumulation of POM nanoclusters in the ischemic penumbra, alleviating oxidative stress and inflammatory injury, effectively inhibiting neuronal apoptosis after brain I/R injury, and restoring neuronal function.

| Nanodelivery strategies for anti-inflammation
The acute systemic inflammation induced by surgery induces or exacerbates ischemic brain injury. The inflammatory response has important implications for stroke susceptibility and prognosis and is involved in the pathophysiological process of stroke. During this process, TNFα, IL-1, IL-6, and C-reactive protein levels are significantly increased. They activate microglia in the brain and stimulate invasive infiltration of peripheral leukocytes, 105 thus accelerating ischemic damage and expanding the infarct area. Therefore, blocking the inflammatory response to alleviate injury is an extremely promising neuroprotective therapeutic strategy. Wang et al. 92 found that 9-AA can act as a novel NR4A1 activator to downregulate the activation levels of microglia and macrophages through the NR4A1/ IL-10/SOCS3 signaling pathway to mitigate inflammatory responses. However, the low therapeutic index and poor water solubility of 9-AA greatly limit its application in vivo. To avoid the adverse effects of 9-AA, they prepared a PEG/cRGD double-modified liposome loaded with 9-AA, which prolonged its blood circulation, and significantly reduced its side effects on the lung. in-depth study of stroke mechanisms, nanotechnology will play an important role in the clinical application of stroke.

CO N FLI C T S O F I NTE R E S T
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.