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. Nanoparticlebased 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, precisionbased treatments that could significantly improve outcomes for stroke patients, thus paving the way for a new era in stroke care and neurological rehabilitation.

Key words: blood–brain barrier, drug delivery systems, ischemic stroke, nanomedicine, nanoparticles, neuroinflammation, neurons, neuroprotection, oxidative stress, phosphatidylinositol 3-kinases