Emerging nanoparticle-based strategies to provide therapeutic benefits for stroke

Abstract

Functional neurological recovery remains the primary objective when treating ischemic stroke. However, current therapeutic approaches often fall short of achieving optimal outcomes. One of the most significant challenges in stroke treatment is the effective delivery of neuroprotective agents across the blood-brain barrier to ischemic regions within the brain. The blood-brain barrier, while essential for protecting the brain from harmful substances, also restricts the passage of many therapeutic compounds, thus limiting their efficacy. In this review, we summarizes the emerging role of nanoparticle-based therapies for the treatment of ischemic stroke and investigate their potential to revolutionize drug delivery, enhance neuroprotection, and promote functional recovery. Recent advancements in nanotechnology have led to the development of engineered nanoparticles specifically designed to overcome the blood-brain barrier, thus enabling the targeted delivery of therapeutic agents directly to the affected brain areas. Preclinical studies have demonstrated the remarkable potential of nanoparticle-based therapies to activate key neuroprotective pathways, such as the phosphoinositide 3-kinase/protein kinase B/cAMP response element-binding protein signaling cascade, which is crucial for neuronal survival, synaptic plasticity, and post-stroke recovery. By modulating these pathways, nanoparticles could mitigate neuronal damage, reduce inflammation, and promote tissue repair. Furthermore, nanoparticles offer a unique advantage by enabling multimodal therapeutic strategies that simultaneously target multiple pathological mechanisms of ischemic stroke, including oxidative stress, neuroinflammation, and apoptosis. This multifaceted approach enhances the overall efficacy of treatment, addressing the complex and interconnected processes that contribute to stroke-related brain injury. Surface modifications, such as functionalization with specific ligands or targeting molecules, further improve the precision of drug delivery, enhance targeting specificity, and prolong systemic circulation, thereby optimizing therapeutic outcomes. Nanoparticle-based therapeutics represent a paradigm shift for the management of stroke and provide a promising avenue for reducing post-stroke disability and improving the outcomes of long-term rehabilitation. By combining targeted drug delivery with the ability to modulate critical neuroprotective pathways, nanoparticles hold the potential to transform the treatment landscape for ischemic stroke. However, while preclinical data are highly encouraging, significant challenges remain in translating these advancements into clinical practice. Further research is needed to refine nanoparticle designs, optimize their safety profiles, and ensure their scalability for widespread application. Rigorous clinical trials are essential to validate their efficacy, assess long-term biocompatibility, and address potential off-target effects. The integration of interdisciplinary approaches, combining insights from nanotechnology, neuroscience, and pharmacology, will be critical if we are to overcome these challenges. Ultimately, nanoparticle-based therapies offer a foundation for innovative, precision-based treatments that could significantly improve outcomes for stroke patients, thus paving the way for a new era in stroke care and neurological rehabilitation.

Keywords: blood–brain barrier; drug delivery systems; ischemic stroke; nanomedicine; nanoparticles; neuroinflammation; neurons; neuroprotection; oxidative stress; phosphatidylinositol 3-kinases.

Figure 1

Nanoparticle-based treatment approaches for ischemic stroke via activation of the PI3K/AKT/CREB pathway. Nanoparticle-based therapeutics can overcome barriers posed by the BBB, enhancing drug delivery for the treatment of ischemic stroke. By activating the PI3K/AKT/CREB pathway, these therapies improve neuroprotection, reduce apoptosis, and promote recovery. This approach presents a viable strategy for enhancing functional restoration and improving clinical outcomes. AKT: Protein kinase B; BBB: blood–brain barrier; CREB: cAMP response element-binding protein; PI3K: phosphoinositide 3-kinase.

Figure 2

Pathophysiological development of hemorrhagic stroke. The damage mechanisms and outcomes of hemorrhagic stroke occur in two phases: primary and secondary damage. Primary damage occurs immediately and includes the formation of a hematoma, tissue compression, and hydrocephalus. In contrast, secondary damage develops over days to weeks and involves processes such as oxidative stress, inflammation, iron toxicity, and perihematomal edema. These overlapping processes contribute to increased intracranial pressure, further exacerbating brain injury.

Figure 3

Nanoparticles in ischemic stroke therapy: mitigating cell death andneurological damage. In ischemic stroke therapy, nanoparticles can reduce cell death by targeting oxidative stress, inflammation, blood–brain barrier breakdown, mitochondrial dysfunction, microglial activation, and the prevention of DNA damage. ROS: Reactive oxidative stress.

Figure 4

Pathophysiological pathways of ischemic stroke: processes induced by molecular interactions. Before being mediated by nanoparticles, oxidative stress (MDA and ROS), excitotoxicity (NMDA), inflammation, and autophagy (AMPK and LC3-II) are all induced by ischemic stroke. Each pathway represents the molecular processes triggered by ischemic stroke, highlighting the intricate interactions between various components in the pathophysiology of the condition. Created with BioRender.com. AMPK: AMP-activated protein kinase; CREB: cAMP response element-binding protein; LC3-II: microtubule-associated protein 1 light chain 3-II; MDA: malondialdehyde; NMDA: N-methyl-D-aspartate; ROS: reactive oxygen species.

Figure 5

Nanoparticles could enhance the treatment of ischemic stroke: Improving neural protection and promoting blood flow recovery. This graphic illustrates the role of nanoparticles in the treatment of ischemic stroke by focusing on the PI3K/AKT/CREB pathway, which enhances neuronal survival. We highlight key stroke-related mechanisms, including interactions with the BBB, vascular blockage, and the application of therapeutic nanoparticles to improve neuroprotection and restore injured brain tissue. The lower section of the graphic emphasizes the potential benefits of nanoparticle-based therapies in stroke recovery, which shows a revival of blood flow. AKT: Protein kinase B; BBB: blood–brain barrier; CREB: cAMP response element-binding protein; PI3K: phosphatidylinositol 3-kinase.

Figure 6

Key molecular processes in ischemic stroke: neuroinflammation, oxidative stress, and excitotoxicity contributing to neuronal damage. These processes engage critical signaling pathways, such as the PI3K/AKT/CREB pathway, which promote neuronal survival and repair. The PI3K/AKT pathway prevents cell death by activating protective signals, while CREB regulates the expression of neuroprotective genes. We also illustrate how engineered nanoparticles facilitate the targeted delivery of therapeutic agents to ischemic brain regions. These nanoparticles are designed to cross the BBB and release drugs in a controlled manner, enhancing the efficacy of stroke treatment while minimizing side effects. AKT/PKB: Protein kinase B; BAD: BCL2 associated agonist of cell death; BBB: blood–brain barrier; BDNF: brain-derived neurotrophic factor; Ca²⁺: calcium ion; CREB: cAMP response element-binding protein; GSK3β: glycogen synthase kinase 3 beta; mTORC1: mechanistic target of rapamycin complex 1; mTORC2: mechanistic target of rapamycin complex 2; NGF: nerve growth factor; PDK1: 3-phosphoinositide-dependent protein kinase 1; PI3K: phosphatidylinositol 3-kinase; PIP2: phospha tidylinositol 4,5-bisphosphate; PIP3: phosphatidylinositol (3,4,5)-trisphosphate; ROS: reactive oxygen species; SOD: superoxide dismutase.

Figure 7

Targeting the PI3K/AKT/CREB pathway with nanoparticles for stroke therapy. Nanoparticles target the PI3K/AKT/CREB signaling pathway, which is involved in stroke, for therapeutic applications. AKT activation inhibits CREB. AKT: Protein kinase B; BCL2: B-cell lymphoma 2; CCL2/3/5: chemokine (C-C motif) ligand 2/3/5; COX-2: cyclooxygenase-2; CRE: cAMP response element; CREB: cAMP response element-binding protein; CRP: C-reactive protein; FOXO: forkhead box O transcription factor; GSK3: glycogen synthase kinase 3; ILs: interleukins; iNOS: inducible nitric oxide synthase; MMP9: matrix metallopeptidase 9; mTOR: mechanistic target of rapamycin; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; P7056K: ribosomal protein S6 kinase beta-1; PI3K: phosphatidylinositol 3-kinase; PRSA40: proline-rich acidic protein 40; RNS: reactive nitrogen species; ROS: reactive oxygen species; TLR-4: toll-like receptor 4; TNF: tumor necrosis factor.