Stroke is associated with a high disability rate due to irreversible neuronal death. The efficacy of conventional stroke treatments, such as thrombolytic and neuroprotective therapies, is often limited by challenges like safety concerns and inefficient drug delivery. The emergence of nanomaterials has opened new possibilities in stroke therapy by improving the pharmacokinetics of drugs, enabling targeted drug accumulation, enhancing therapeutic efficacy, and minimizing side effects.

Related Services

• Nanoparticle-Based Drug Delivery System Development for Stroke

Ace Therapeutics is a stroke-focused CRO offering customized nanoparticle-based drug delivery system development services. Our experienced team of scientists can help clients develop feasible and effective nanoparticle-based drug delivery systems to deliver stroke drugs across the BBB to targeted ischemic brain regions. Additionally, we can leverage nanotechnology to assist clients in designing contrast agents that enhance the diagnostic capabilities of CT and MRI scans for stroke detection.

Overview of Nanomaterials in Stroke

Nanomaterials are defined as materials with a diameter of 100 nm or less. The smaller the nanomaterial, the larger its surface area-to-volume ratio, which enhances its interaction efficiency with tissue cells. Their unique physical structure gives rise to distinctive effects, including photoelectromagnetic thermal effects, side effects, and surface interface effects, which play a crucial role in the diagnosis and treatment of stroke.

Under normal physiological conditions, the blood-brain barrier (BBB) restricts the entry of macromolecules such as peptides, proteins, and nucleic acids into the brain, posing significant challenges for stroke diagnosis and therapy. However, the small size and structural properties of nanomaterials enable macromolecular substances to bypass the BBB, effectively targeting brain infarction areas and interacting with the central nervous system (CNS).

In diagnostic imaging, nanomaterials have been developed into advanced imaging probes for detecting vascular infarctions and monitoring therapeutic progress. In drug delivery, nanomaterials serve as efficient carriers, enabling targeted delivery to the CNS. Current delivery pathways include nanoparticles, liposomes, nanogels, dendrimers, and other nanostructures.

Moreover, nanotechnology is driving the creation of next-generation nanotherapeutic tools by integrating genetic engineering. These tools selectively accumulate at sites of cerebral infarction, aiding in the treatment of ischemic stroke by reducing inflammation, promoting collateral circulation, minimizing cerebral edema, and restoring oxygen and blood flow to brain tissue.

Fig. 1 Nanomaterials for stroke diagnosis and treatment. (Liu, et al., 2024)

Nanomaterials as a Diagnostic Tool in Stroke

The Application of Nanomaterials in Marker Detection

Nanomaterials are increasingly used in the detection of stroke biomarkers, significantly enhancing the sensitivity and accuracy of diagnostic tests. Important biomarkers such as neuron-specific enolase (NSE), cardiac troponin (cTnI), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are critical for diagnosing ischemic stroke. Nanomaterials improve detection through optimized detection reagents, resulting in better performance. For example:

• Gold nano bipyramids (Au NBP) are used in a biosensor for detecting NSE, with distinct fluorescence changes that allow for accurate and stable assessments across a wide range of NSE concentrations.
• Quantum dots (QDs), due to their superior optical properties, have been incorporated with aptamers to create a biosensor for the sensitive detection of cTnI, improving both accuracy and specificity in clinical diagnostics.
• Co-N-C nanosheets are used in an electrochemical immunosensor for NT-proBNP, offering enhanced signal amplification, biocompatibility, and excellent sensitivity and selectivity.

The Application of Nanomaterials in Imaging Devices

Computerized tomography (CT) and magnetic resonance imaging (MRI) are indeed the primary imaging techniques for stroke diagnosis due to their ability to provide detailed and accurate brain images. Nevertheless, these techniques have unavoidable limitations, which helped to facilitate research on the application of nanotechnology. CT is commonly used to differentiate between ischemic and hemorrhagic strokes and to assess brain regions with varying perfusion levels. However, alkaline earth metal-based nanocontrast agents are being employed to enhance the spatial resolution of CT images. Similarly, MRI, considered the "gold standard" for stroke imaging, is being improved with the use of nanoparticles (NPs) to boost image contrast and sensitivity, addressing the limitations of conventional MRI techniques. These advancements in nanotechnology are enhancing diagnostic capabilities, enabling more accurate and efficient stroke diagnosis.

Fig. 2 The application of nanoparticles in MRI. (Liu, et al., 2024)

Nanomaterials for Delivery of Therapeutics for Stroke

Nanocarriers show potential as drug delivery systems for the treatment of stroke. They have the ability to resist drug degradation, enhance drug metabolism kinetics, and improve neurovascular pathways. Nanoparticles can be modified to increase the likelihood and concentration of drug delivery to the ischemic site by crossing the blood-brain barrier. A variety of nanocarriers can target the enzyme tissue-type plasminogen activator (tPA), neuroprotective therapies (e.g., neural stem cells, hypoxia-inducible factors), antioxidants, and anti-inflammatory agents to ischemic regions of the brain. Additionally, in stroke gene therapy, nanomaterials are used to precisely deliver therapeutic genes, improve the efficiency of gene transfection, protect genes from degradation, and enable targeted, effective treatment of brain tissue.

Polymeric Nanocarriers

Polymeric nanocarriers, such as PLGA (poly(lactic-co-glycolic acid)), are widely used in biomedical applications due to their biodegradability and nontoxicity. PLGA nanocarriers release drugs through hydrolysis, which breaks down the polymer into smaller molecules, facilitating drug release. These nanocarriers are effective for delivering antioxidants and neuroprotective agents. PEG-based nanoparticles are commonly used for drug delivery across the blood-brain barrier (BBB) to the infarct site. Coating nanoparticles with polysorbate 80 enhances BBB penetration through receptor-mediated endocytosis. Additionally, polymeric micelles, like PEG-b-poly(methyl styrene) block copolymers, are gaining attention for their ability to self-assemble and be used in stroke therapy.

Lipid-based Carriers

Lipid-based carriers, particularly liposomes, are commonly used for drug delivery in ischemic stroke therapy. These carriers are made from amphipathic lipids and self-assemble into vesicular structures. Liposomes for stroke treatment typically include phosphatidylserine (PS), dioleoylphosphatidylethanolamine (DOPE), and cholesterol. Surface modifications, such as incorporating PEG, can enhance liposome stability and prolong their circulation time, improving biodistribution and bioavailability. Stimuli-responsive liposomes have also been developed to release therapeutic agents in a controlled manner.

Other Nanocarriers

Various nanocarriers have been explored for stroke therapy, each with unique features that enable targeted drug delivery. Silica-based ceramic carriers, for example, have a highly porous network and can be functionalized for specific applications, such as delivering tPA to thrombus sites. Carbon-based nanomaterials, including graphene and carbon nanotubes, have biocompatible surfaces and are used in different therapeutic applications, such as stem cell delivery and oxidative stress mitigation. Exosomes, mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs) are also employed as delivery vehicles, demonstrating promising results in enhancing angiogenesis and neural regeneration in ischemic stroke models.

Additionally, platinum (Pt) nanoparticles (NPs) act as scavengers for reactive oxygen species (ROS), alleviating oxidative stress during ischemia. Xenon-encapsulated liposomes, delivered through ultrasound guidance, have neuroprotective properties, while adenosine nano assemblies and single-walled nanotubes show improvements in neuro deficits and neuroinflammatory responses. Multi-walled carbon nanotubes (MWCNT) can increase neurite outgrowth and serve as carriers for small interfering RNA (siRNA) to silence apoptotic genes.

Fig. 3 Two nanoparticle design strategies for targeted stroke therapy. (Wang, et al., 2024)

Challenges of Nanomaterials in Stroke Research

Biosafety of Nanomaterials

Nanomaterials hold significant potential for stroke applications, particularly in diagnostics, imaging, drug delivery, and therapy due to their exceptional physicochemical properties. However, prolonged accumulation in tissues can lead to toxicity, limiting their widespread clinical use. A deeper understanding of their design and metabolic pathways is crucial for advancing their use in stroke treatment.

The Instability of Nanomaterial-marker Combinations

Nanomaterials have the potential to enhance the diagnosis of stroke by detecting subtle changes in lesion areas. However, the instability of nanomaterial-marker combinations can lead to premature removal of nanomaterials from the body. To address this, improving the stability of these combinations is essential to ensure that nanomaterials remain functional in the blood for diagnostic purposes.

Preparation Method of Nanomaterials

The therapeutic effects and side effects of nanomaterials are influenced by their preparation method, so enhancing reproducibility and control during production is key.

1. Liu, Y., et al. (2024). Nanomaterials for stroke diagnosis and treatment. iScience.
2. Wang, Y., et al. (2024). The role of nanomaterials in revolutionizing ischemic stroke treatment: Current trends and future prospects. iScience.
3. Sarmah, D., et al. (2021). Nanotechnology in the diagnosis and treatment of stroke. Drug discovery today, 26(2), 585-592.