Aim: This review provides a systematic evaluation of 94 stem cell clinical trials to treat neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Methods: Data were collected from using relevant search terms, focusing exclusively on stem cell therapy. Of the 8000+ participants in these trials, nearly 70% were enrolled in AD‐related studies. Only three Phase 3 studies were conducted, and most trials were in the early phases (Phases 1 and 2). Mesenchymal stem cells, neural stem cells, induced pluripotent stem cells, and embryonic stem cells are used the most to treat neurodegenerative diseases. This review also explores the emerging fields of preclinical and clinical investigations of stem cell‐derived exosome‐based therapies for neurodegenerative diseases. Results: Exosomes can cross the blood–brain barrier to deliver therapeutic molecules directly to the brain, offering a less invasive alternative to stem cell transplantation. Mesenchymal stem cell‐derived exosomes, in particular, have demonstrated significant potential in preclinical models by reducing neuroinflammation, oxidative stress, and promoting neuronal regeneration. Additionally, recent advances in exosome engineering, including surface modifications, therapeutic agent loading, and transgenic modifications, have improved targeting, stability, blood–brain barrier delivery, and neural cell interactions, enabling targeted and effective treatment. Exosome‐based therapies are in the preliminary phases of clinical investigation, with only three clinical trials. Conclusion: Given the increasing interest in exosome therapy, clinical investigations are expected to increase. This growth will be driven by ongoing advancements in exosome technology, a deeper understanding of their therapeutic potential, and escalating demand for innovative treatment strategies for neurodegenerative diseases.

Neuroinflammation is central to the progression of neurodegenerative diseases (NDs), with microglia contributing through the release of pro-inflammatory and oxidative mediators. Although quercetin (Que) possesses potent anti-inflammatory and antioxidant properties, its clinical application is limited by poor solubility and bioavailability. Umbilical cord mesenchymal stem cells (UC-MSCs)-derived exosomes (Exo) offer a promising delivery system to enhance Que efficacy. This study investigated the anti-inflammatory effects of Que-loaded Exo (Que-Exo) using an in vitro neuroinflammation model. Exo were isolated from UC-MSC-conditioned media via ultracentrifugation and loaded with Que through sonication. Characterization of Exo and Que-Exo was performed using dynamic light scattering, zeta potential analysis, transmission electron microscopy, and western blotting. In vitro release and cellular uptake studies assessed Que-Exo release profiles and their internalization by HMC3 microglial cells. Neuroinflammation was induced in HMC3 cells using lipopolysaccharide (LPS). The effects of Que-Exo on pro-inflammatory cytokine and enzyme expression, nitric oxide (NO) production, and inflammatory signaling pathways were evaluated using flow cytometry, the Griess assay, and western blotting. In vitro release from Que-Exo demonstrated improved stability and controlled delivery, while fluorescence imaging confirmed efficient uptake of Que-Exo by HMC3 cells. Mechanistically, Que-Exo inhibited NF-κB nuclear translocation, a key regulator of pro-inflammatory mediator transcription. Que-Exo pretreatment significantly reduced TNF-α, IL-6, iNOS, and COX-2 expression and suppressed NO synthesis in LPS-stimulated cells. Overall, Que-Exo exhibited superior anti-inflammatory activity compared to Exo and free Que, highlighting the synergistic effect of exosomal delivery in enhancing Que bioavailability and therapeutic efficacy against neuroinflammation. Graphical Abstract

Epilepsy is a persistent neurological disorder characterized by repeated, spontaneous seizures that arise without a specific cause. These seizures result from abnormal electrical activity in the brain, leading to a range of symptoms, from brief periods of unconsciousness or minor sensory disturbances to severe convulsions. The management of epilepsy remains a significant challenge, as current treatment modalities, primarily involving antiepileptic drugs and surgical interventions to remove seizure foci, often provide adequate control for a substantial portion of patients. For this reason, stem cell therapies have become a hopeful approach because of their ability to potentially restore and renew impaired neural networks, which is particularly relevant for neurological disorders like epilepsy. This review investigates the present state of stem cell therapies in epilepsy, analyzing distinct types of stem cells, their mode of action, preclinical and clinical trials, as well as future research prospects.