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Toljan, K.; Ashok, A.; Labhasetwar, V.; Hussain, M.S. Nanotechnology in Stroke. Encyclopedia. Available online: https://encyclopedia.pub/entry/42087 (accessed on 20 December 2025).
Toljan K, Ashok A, Labhasetwar V, Hussain MS. Nanotechnology in Stroke. Encyclopedia. Available at: https://encyclopedia.pub/entry/42087. Accessed December 20, 2025.
Toljan, Karlo, Anushruti Ashok, Vinod Labhasetwar, M. Shazam Hussain. "Nanotechnology in Stroke" Encyclopedia, https://encyclopedia.pub/entry/42087 (accessed December 20, 2025).
Toljan, K., Ashok, A., Labhasetwar, V., & Hussain, M.S. (2023, March 10). Nanotechnology in Stroke. In Encyclopedia. https://encyclopedia.pub/entry/42087
Toljan, Karlo, et al. "Nanotechnology in Stroke." Encyclopedia. Web. 10 March, 2023.
Nanotechnology in Stroke
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11030780

Stroke is a leading cause of death, long-term disability, and socioeconomic costs, highlighting the urgent need for effective treatment. During acute phase, intravenous administration of recombinant tissue plasminogen activator (tPA), a thrombolytic agent, and endovascular thrombectomy (EVT), a mechanical intervention to retrieve clots, are the only FDA-approved treatments to re-establish cerebral blood flow. Due to a short therapeutic time window and high potential risk of cerebral hemorrhage, a limited number of acute stroke patients benefit from tPA treatment. Different attributes of nanoparticles are also being explored to develop a multifunctional thrombolytic agent that, in addition to a thrombolytic agent, can contain therapeutics such as an anti-inflammatory, antioxidant, neuro/vasoprotective, or imaging agent, i.e., a theragnostic agent. 

nanoparticles drug delivery thrombolysis drug targeting reperfusion injury oxidative stress

1. Nanoconjugates to Protect the Brain from I/R Injury

In stroke, protecting cerebral vasculature is an important target to prevent the breakdown of the BBB, which could lead to inflammatory cells migrating to the brain parenchyma, oxidative stress, and edema that can further trigger a downstream secondary reperfusion injury. Even if the clot is successfully resolved, reperfusion injury still entails a pro-inflammatory cascade akin to ischemic tissue changes [1]. Besides the reperfusion injury, hemorrhagic conversion of ischemic stroke represents another possible early sequela, either as a spontaneous event or after recanalizing therapy use. In such instances, subsequent pathophysiology is shared with the course of parenchymal hemorrhagic stroke. Therefore, the development of effective combination therapy for stroke that provides not only thrombolysis but also attenuates secondary I/R injury is also necessary.

1.1. Nanoparticles with Antioxidant Agents

Metal nanoparticles acting as free radical scavengers such as cerium, platinum, selenium, and gold nanoparticles have shown protective effects in animal I/R injury models by regaining redox balance and preserving mitochondrial integrity [2][3]. Experiments also included the use of a targeting ligand with cerium nanoparticles such as integrin αvβ3, which is upregulated during ischemic injury [4]. These conjugated nanoparticles demonstrated better outcomes in terms of improved neurologic impairment scores, decreased infarction volume, decreased BBB disruption, oxidative stress, and neuronal apoptosis in the MCAO rat model [5]. Additional efforts included combining cerium nanoparticles with edaravone, another antioxidant, for a synergistic effect in neutralizing ROS [6]. Natural antioxidants such as resveratrol, a polyphenol antioxidant [7] resveratrol conjugated to low-density lipoprotein receptor [8], curcumin [9], nanozyme [10], melanin nanoparticle [10], melanin nanoparticles combined with MSC [11], betulinic acid (BA) [12], and glyburide-loaded BA [13] have been produced a protective effect in various models assessing their effectiveness against I/R injury-related oxidative stress.
In the efforts to address the issue of I/R injury, researchers encapsulated antioxidant enzymes, either catalase (nano-CAT) or superoxide dismutase (nano-SOD) or a combination of both (nano-SOD/CAT) in biodegradable, PLGA-based nanoparticles. Researchers tested them in vitro, both in neurons and astrocytes, for their protective effect against hydrogen peroxide-induced oxidative stress [14][15]. The subsequent studies were carried out in the MCAO rat model of I/R injury [16] and in a thromboembolic model [17]. The treatments were given via the carotid artery at the time of reperfusion. In the thromboembolic model, it was a sequential treatment, tPA, followed by nano-SOD/CAT. The advantage of using antioxidant enzymes is their catalytic mechanism of action; hence they are very effective in neutralizing ROS even at low doses [18]. The compounds with antioxidant properties are inactivated after interaction with ROS, necessitating repeated dosing to maintain their therapeutic levels, which could be challenging in a clinical setting.
The data demonstrated the protective effect of nano-SOD and nano-CAT in neurons [14] and astrocytes [15] from oxidative stress in cell culture experiments. In the MCAO rat model, many aspects of I/R injury were inhibited following treatment with enzyme-loaded nanoparticles, which had favorable effects including protection of the BBB, inhibition of edema, reduction in infarct volume, improved neurological recovery, and long-term survival [16]. Interestingly in the embolic stroke model, tPA-only treatment was seen to inhibit the migration of progenitor cells and stem cells from the subventricular zone, but the combination treatment, i.e., tPA followed by nano-CAT/SOD, restored the above cellular activities, promoting neurogenesis [17]. In the above study, the sequential treatment of tPA followed by nano-CAT/SOD inhibited edema, indicating protection of BBB from I/R injury [17]. Since the initial studies, another group has shown similar efficacy with antioxidant enzyme-loaded nanoparticles [19]. Recent efforts include developing ROS-targeting nanomedicines containing an antioxidant agent to achieve target-specific delivery to the ischemic tissue [20]. Nanozyme, a polymer complex of antioxidant enzymes, has similarly shown the protective effect from I/R injury, including protecting neurons and the cerebral vasculature [21][22].

1.2. Nanoparticles with Anti-Inflammatory Agents

To overcome post-ischemic neuro-inflammatory damage, various anti-inflammatory conjugates have been studied in stroke models. For example, the liposomal cyclosporine A [23] and berberine nano micelles [24] have been reported to reduce microglial immunoreactivity, inflammatory responses, and infarct lesion volumes. Nanoparticles conjugated with monocyte membrane and rapamycin have been shown to inhibit the proliferation of neutrophils [25], reversing the pattern of inflammatory cytokines expression, resulting in improved neurological function [26]. In a few instances, the compound has pleiotropic effects. For example, bioactive nanoparticle engineered from a pharmacologically active oligosaccharide material (termed as TPCD), prepared by covalently conjugating a radical-scavenging compound (Tempol) and phenylboronic acid pinacol ester (PBAP) on β-cyclodextrin, decreased infarct volume and accelerated recovery of neurological function in the MCAO mice model, which was achieved by its simultaneous antioxidative, anti-inflammatory, and antiapoptotic effects [27].

2. Mechanical and Biological Stimulus

To loosen the clot or to improve the efficacy of thrombolytic agents, external mechanical stimuli such as ultrasound (sonothombolysis) [28][29], or external magnetic field with formulations containing magnetic nanoparticles carrying thrombolytic agents, have been explored. It is feasible to guide magnetic nanoparticles to the occlusion site using an external magnetic field to enhance the transport of tPA to the thrombus and increase the tPA-mediated thrombolysis [30][31][32]. The use of thrombus-targeting liposomal nanobubbles with concurrent high-intensity ultrasound (4.0 W/cm2) in a rabbit model of iliofemoral artery thrombosis showed recanalization in 90% of the animals as compared to 40% with tPA, or 20% with platelet non-specific nanobubbles and the same intensity of ultrasound [28]. Clinical trials with microbubbles and ultrasound increased the rate of recanalization and better outcomes in younger patients but with an increased risk of hemorrhagic complications or brain edema [33][34]. In another study, thrombus-targeting magnetic nanoparticles were developed by functionalizing iron oxide nanoparticles with an antibody recognizing activated integrin αIIbβ3. In this case, magnetic hyperthermia made the clot susceptible to the tPA-mediated thrombolysis [35].
Shear-activated nanoparticles taking the advantage of the distortion of the bloodstream caused by the clot itself, or aggregating nanoparticles releasing the tPA at the site of the stenosis, successfully recanalized blood vessels in the mouse model of embolism [36]. A similar approach has been explored by using a temporary endovascular bypass with a shear-activated nanotherapeutic that releases tPA when exposed to high levels of hemodynamic stress at sites of partial vascular occlusion in a rabbit model [37]. Anti-fibrin antibody targeting is one of the most effective methods for efficiently delivering tPA to the thrombus. Anti-fibrin antibodies deliver t-PA to the thrombus site in an inactive state, subsequently triggering its controlled activation, thereby reducing the risk of bleeding [38]. Zhang et al. have developed a self-assembling nanoformulation containing a photothermal sensitizer and a photothermal-activable nitric oxide donor. Following laser exposure, nanoformulation generated heat that facilitated its penetration into the clot and also generated nitric oxide. In animal models of acute ischemic stroke, the nanoformulation demonstrated better thrombolysis than the nanoparticle formulation without the photoactivation feature, and the produced nitric oxide prevented the recurrence of the clot formation [39].

3. Interactions at the BBB

Blood brain barrier integrity is compromised in the setting of acute stroke, but also following application of standard recanalizing therapies [40]. Mechanical thrombectomy causes local physical injury [41], while thrombolytics induce physiological changes which make the BBB more permeable [42]. Even in case of successful recanalization, I/R injury contributes to a variable degree of BBB compromise [43]. All these factors should be considered when investigating the application of nanoparticles to ameliorate some of the changes caused by ischemia as the primary event and associated secondary processes. Modifying nanoparticles by decreasing their size, maintaining a net positive charge, or by conjugating with ligands which are transcytosis transporter substrates, enhances the transport across an intact BBB [44]. By conjugation with cell-penetrating ligand, nanoparticles bypass the transcytosis pathway, while a formulation enabling a prolonged half-life further enhances the overall delivery to the target tissue, i.e., movement across BBB [44]. In the setting of acute injury which compromises the integrity of BBB, nanoparticles are able to penetrate the injured tissue site more easily [45]. The latter has been shown to occur in the setting of metabolic insults such as hypoxia [46], but experimental BBB disruption with osmotic, mechanical (ultrasound), or magnetic stimulus leading to greater NP penetrance has also been demonstrated [47]. In a clinical setting, this could be translated as therapeutic use of ultrasound to temporarily increase BBB permeability [48], while the NP-based therapy would be administered.

4. Clinical Application

Although nanotechnology is currently not approved for treatment of acute stroke or for neurorehabilitation, a considerable number of in vivo animal model studies and limited human studies offer hope and opportunities for translation into actual tools for human clinical practice (Table 1). There are multiple experiments which show how nanotechnological compounds could address stroke-associated pathophysiological processes (Table 1).
Nanoparticles with paramagnetic properties have been used as conjugates to target specific proteins in acute stroke as well as atherosclerosis. Such nanoconjugates can target intracellular or extracellular targets. Initial studies showed that smaller particles such as ultrasmall superparamagnetic iron oxide nanoparticles (USPION), with a size of less than 50 nm, have a longer half-life than larger ones, yet contrast labeling is superior with larger particles [49]. In a proof-of-concept study involving 11 subjects scheduled for carotid endarterectomy [50]. Kooi et al. reported that administration of USPION was associated with subsequent nanoparticle intake in high-risk or ruptured plaque, which was visualized with MRI and later confirmed by histopathology. In the ATHEROMA study [51], Ferumoxtran-10 as a USPION was successfully used to assess plaque status following statin use as part of the observed intervention. To boost the quality as contrast enhancers while also maximizing their additional clinical potential, micro-sized paramagnetic iron oxide nanoparticles (MPION) conjugated with antibodies aimed at receptors associated with endothelial activation, a process occurring in acute stroke, have been developed. Conjugates of such size, at the verge of nano- and microtechnology, were able to bind to activated endothelial surface proteins, e.g., vascular cell adhesion molecule-1 (VCAM-1), and act as adequately specific and sensitive contrast agents [52]. In a similar fashion, a MPION conjugate targeting P-selectin [53], or a different one targeting intercellular adhesion molecule-1 (ICAM-1) [54], were used to detect activated endothelium. This could help detect different phases of stroke, even transient ischemic attack (TIA)-related pathophysiology. Citicoline, a substance with neuroprotective effects, was combined with an immunoliposome targeting VCAM-1 [55]. It was successfully used as a theragnostic agent when the final nanoparticle reached the activated endothelium and concurrently represented a signal on chemical exchange saturation transfer (CEST) MRI. The presented capabilities would be invaluable for establishing stroke etiology, assessment of vascular inflammation and tissue at risk, or guiding further diagnostics and treatment. Moreover, nanoconjugates could also represent efficacy biomarkers when studying new or established stroke therapies.
Safety remains as a concern when considering nanoparticles for use in human subjects. Ideally, nanoconjugates should be biodegradable and non-toxic. Their profile should be favorable in terms of risks and benefits, and they indeed would represent a superior diagnostic or therapeutic modality as compared to the current standard. Targets identified in animal studies do not necessarily translate equally in the setting of the human body environment. The use of iron containing nanoparticles in acute inflammatory state may be limited by the possibility of local oxidative reaction following cellular intake. Therefore, preferred clearance could favor renal route or by enzymatic cleavage and phagocytic or endocytic mechanisms with ultimate non-toxic metabolism.
Table 1. Nanoparticles and nanoconjugates investigated for potential applications in ischemic stroke diagnosis, treatment, and study of cerebrovascular pathophysiology.
Nanoparticle or Nanoconjugate Used Study Subjects Objective Reference
Ultrasmall superparamagnetic iron oxide particles Human Detection of high-risk or ruptured carotid artery plaque [50]
Human Assessment of carotid plaque status following intervention (statin use) [51]
Iron oxide microparticle conjugated with specific antibodies (P-selectin, ICAM-1) Mouse Detection of abnormal cerebrovascular endothelium due to transient ischemia [53]
Mouse Detection of abnormal endothelium and migrating leukocytes in the setting of cerebrovascular injury (infarct, reperfusion) [54]
Iron oxide nanoparticles with an antibody recognizing activated integrin αIIbβ3 Ex-vivo study (human blood clot) Improved thrombolytic binding and affinity [35]
Liposomal citicoline conjugated with VCAM-1 Mouse Use of conjugate as a theragnostic agent [55]
Liposomal tacrolimus Rat Use as neuroprotectant to reduce inflammation [56]
Liposomal cyclosporine A Rat Reduction in infarct lesion size and inflammatory activity [23]
Berberine nano micelles Rat [24]
PLGA-based nanoparticles with nano-catalase or superoxide dismutase Mouse Decrease in I/R injury with reduction in infarct volume, protection of the BBB integrity, and improved recovery [16]
Mouse Decrease in I/R injury and amelioration of thrombolysis related decreased migration of subventricular zone stem cells [17]
Cerium, platinum, selenium, or gold nanoparticles Rat Improving redox imbalance and preserving mitochondria [2]
[3]
Cerium nanoparticles with edaravone Rat Decreased oxidative injury [6]
Resveratrol conjugated to LDL receptor Ex vivo study (rat cell cultures) Reduction in I/R related injury [8]
Melanin loaded nanoparticles Mouse [11]
Glyburide-loaded betulinic acid nanoparticles Rat [12]
Encapsulated or conjugated tPA;
PEGylated liposomes, silica-coated or gold nanoparticles, polymeric nano-constructs		 Rat Thrombolytic stability to enhance drug delivery to the target [57]
Mouse [58]
[59]
In vitro and mouse [60]
Nanoparticles conjugated with monocyte membrane and rapamycin Rat Reduction in neutrophil proliferation [25]
Lipid nanoparticle conjugated with siRNA against Toll-like receptor-4 Mouse Reduction in inflammation-induced microglial activation [26]
Nanoparticle TPCD (Tempol with phenyloboronic acid pinacol ester and β-cyclodextrin) Mouse Decrease in infarct volume and acceleration of recovery [27]
Nanoplatelet conjugated with neuroprotectant (ZL006e) Rat Reduction in infarct area and improved drug delivery across BBB [61]
Platelet membrane-cloaked polymeric nanoparticles with tPA Mouse Improvement of thrombolytic profile with less hemorrhagic complications [62]
MnCO3@BSA-ICG nanoconjugate Mouse Infarct area detection [63]
NanoGd conjugate Cynomolgus macaques BBB permeability assessment [64]
MSC-derived exosome nanovesicles combined with gold nanoparticles Mouse Targeted delivery to injured tissue [65]
Nanoparticles with fucoidan Mouse Infarct area detection, improved thrombolysis [66]
L-carnosine peptide conjugated magnetic nanoparticles loaded with dexamethasone In vitro Delivery of dexamethasone across BBB model [67]
Abbreviations: BBB—blood brain barrier; BSA-ICG—bovine serum albumin and indocyanine green; Gd—gadolinium; I/R—ischemia/reperfusion; ICAM-1—intercellular adhesion molecule-1; LDL—low density lipoprotein; MSC—mesenchymal stem cells; PEG—polyethylene glycol; PLGA—poly (lactic-co-glycolic acid); siRNA—small interfering ribonucleic acid; tPA—tissue plasminogen activator; VCAM—vascular cell molecule-1.

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Karlo Toljan
, Anushruti Ashok , Vinod Labhasetwar , M. Shazam Hussain
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