Extracellular vesicles (EVs) have emerged as pivotal mediators in neurological diseases, showcasing multifaceted potential roles ranging from pathogenesis to diagnosis. These nano-sized membranous structures, released by various cell types including neurons, astrocytes, and microglia, encapsulate a diverse cargo of proteins, lipids, RNA species, and even DNA fragments. In neuropathology, EVs contribute significantly to intercellular communication within the central nervous system (CNS), influencing physiological or pathological cascades. Through the transfer of bioactive molecules, EVs modulate neuroinflammation, neuronal survival, synaptic plasticity, and the propagation of protein aggregates characteristic of neurodegenerative disorders. Moreover, their presence in biofluids such as cerebrospinal fluid (CSF), blood, and urine reflects the pathophysiological state of the CNS, offering a window into the diagnosis, monitoring and treatment of neurological diseases. Recent advancements in EV isolation techniques, coupled with high-throughput omics technologies, have facilitated the profiling of EV cargo, enabling the identification of disease-specific biomarkers with high sensitivity and specificity. This review explores the intricate roles of EVs in neuropathology, highlighting their involvement in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and other neurological disorders. Furthermore, it delves into the diagnostic potential of EVs, discussing current challenges and prospects in harnessing EV-derived biomarkers for precision medicine in neurology. Ultimately, understanding the biology of EVs in neurological contexts promises transformative insights into disease mechanisms and therapeutic strategies, paving the way for innovative diagnostic tools and targeted interventions in clinical practice.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with impaired cognitive function and memory loss. Currently, available therapeutics can effectively alleviate the symptoms of AD, but there is a lack of treatment to halt the progression of the disease. In recent years, exosomes have gained much attention due to their involvement in various neurological disorders. Exosomes are small extracellular vesicles comprising lipids, proteins, DNA, non-coding RNA, and mRNAs, can carry various therapeutic molecules, and are potential drug delivery vehicles. Exosomes are known as a double-edged sword due to their involvement in both the pathogenesis and management of AD. This review explores the function of exosomes in the pathophysiology, treatment, and diagnosis of AD, also emphasizing their potential as a targeted drug delivery carrier to the brain. This review seeks to provide novel perspectives to understand better the onset, targeted treatment, and diagnosis of AD using exosomes.

Pulmonary fibrosis (PF) is a disease with high morbidity and mortality rates, but effective treatment options are extremely limited. Mesenchymal stem cells (MSCs) and their derivatives show promise as potential therapeutics for PF. However, the underlying mechanisms responsible for these beneficial effects remain poorly understood. The objective of this study was to elucidate the specific mechanism through which microvesicles derived from human umbilical cord MSCs (MSC-MVs) alleviate PF.

The effects of MSC-MVs on PF in bleomycin (BLM)-induced mice were assessed via histological staining, flow cytometry, and enzyme-linked immunosorbent assays (ELISAs). The potential therapeutic target was identified via RNA sequencing (RNA-seq) analysis, followed by validation via real-time quantitative polymerase chain reaction (RT‒qPCR), ELISAs, scratch testing, and western blotting (WB).

MSC-MVs significantly attenuated collagen fiber deposition and downregulated the expression of extracellular matrix components in the lungs of the BLM-induced mice. Moreover, this treatment substantially ameliorated lung inflammation by reducing the monocyte‒macrophage ratio and the TNF-α and IL-6 levels. Further analyses revealed that MSC-MVs inhibited the classic chemotactic CCL2/CCR2 axis of monocyte‒macrophages, leading to reduced recruitment of monocytes‒macrophages to the lungs, which decreased lung inflammation and prevented fibrotic progression. Both in vitro and in vivo findings demonstrated that MSC-MVs suppressed ERK1/2 phosphorylation followed by decreased CCL2 production to modulate monocyte-macrophage migration.

Our findings demonstrate that the protective effect of MSC-MVs against BLM-induced lung toxicity was achieved through the inhibition of the ERK1/2 signaling pathway, leading to the suppression of CCL2 expression and subsequent modulation of monocyte-macrophage migration, thereby establishing a theoretical basis for the effect of MSC-MVs in PF.

Exosomes, nanosized extracellular vesicles released by various cell types, are intensively studied for the diagnosis and treatment of cancer and neurodegenerative diseases, and they also display high usability in regenerative medicine. Emphasizing their diagnostic potential, exosomes serve as carriers of disease-specific biomarkers, enabling non-invasive early detection and personalized medicine. The cargo loading of exosomes with therapeutic agents presents an innovative strategy for targeted drug delivery, minimizing off-target effects and optimizing therapeutic interventions. In regenerative medicine, exosomes play a crucial role in intercellular communication, facilitating tissue regeneration through the transmission of bioactive molecules. While acknowledging existing challenges in standardization and scalability, ongoing research efforts aim to refine methodologies and address regulatory considerations. In summary, this review underscores the transformative potential of exosomes in reshaping the landscape of medical interventions, with a particular emphasis on cancer, neurodegenerative diseases, and regenerative medicine.

Extracellular vesicles (EVs) convey complex signals between cells that can be used to promote neuronal plasticity and neurological recovery in brain disease models. These EV signals are multimodal and context-dependent, making them unique therapeutic principles. This review analyzes how EVs released from various cell sources control neuronal metabolic function, neuronal survival and plasticity. Preferential sites of EV communication in the brain are interfaces between pre- and postsynaptic neurons at synapses, between astrocytes and neurons at plasma membranes or tripartite synapses, between oligodendrocytes and neurons at axons, between microglial cells/macrophages and neurons, and between cerebral microvascular cells and neurons. At each of these interfaces, EVs support mitochondrial function and cell metabolism under physiological conditions and orchestrate neuronal survival and plasticity in response to brain injury. In the injured brain, the promotion of neuronal survival and plasticity by EVs is tightly linked with EV actions on mitochondrial function, cell metabolism, oxidative stress and immune responses. Via the stabilization of cell metabolism and immune balance, neuronal plasticity responses are activated and functional neurological recovery is induced. As such, EV lay the ground for neuronal plasticity.

Neuroinflammation triggered by microglia activation is hallmark of autism spectrum disorder (ASD), and this process includes crucial metabolic reprogramming from oxidative phosphorylation to glycolysis, which may cause neuron loss and functional impairment. The inhibitory immune checkpoint programmed cell death protein 1 (PD-1) on immune cells is an important target for tumor immunotherapy. However, the immunomodulatory effects of PD-1 in ASD remains to be elusive. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) exhibit immunomodulatory capabilities in a range of neurological diseases. Our findings indicated the expression of PD-L1 on MSC-EVs, potentially facilitating signaling to PD-1-expressing microglia. Here, we showed how MSC-EVs activated of PD-L1/PD-1 axis and ameliorated glycolysis, neuroinflammation and autism-like behaviors. After first detecting elevated glycolysis and neuroinflammation in prefrontal cortex (PFC) tissue from the maternal immune activation (MIA) mice, we also demonstrated that PD-1 expression level was upregulated in microglia. Following given MSC-EVs carried PD-L1 into adult MIA offspring mice via intranasal administration, which bound with PD-1 on microglia and then the autism-like behaviors were alleviated as well. Further experiments verified that MSC-EVs could decreased the level of glycolysis and neuroinflammation by PD-1/ERK/HIF-1α pathway in the primary microglia in PFC of MIA offspring mice. Pharmacological blockade and genetic inhibition of PD-1 could weaken the effect of MSC-EVs and aggravate microglial dysfunction, glycolysis and autism-like behaviors in MIA offspring mice. Futhermore, PD-L1 deficient weakened the effect of MSC-EVs on neuroinflammation, glycolysis and autism-like behaviors in MIA offspring mice. Our research indicated the significant immunomodulatory capabilities of MSC-EVs, which play an important role in reprogramming microglial glucose metabolism and suppressing neuroinflammation in ASD. By activating the PD-L1/PD-1 axis and inhibiting the downstream ERK/HIF-1α pathway, MSC-EVs were found to alleviate autism-like behaviors, which revealing a novel pathological mechanism and offering promising therapeutic insights into ASD.

Extracellular vesicles (EVs) are membrane vesicles secreted by all types of cells, including bacteria, animals, and plants. These vesicles contain proteins, nucleic acids, and lipids from their parent cells and can transfer these components between cells. EVs have attracted attention for their potential use in diagnosis and therapy due to their natural properties, such as low immunogenicity, high biocompatibility, and ability to cross the blood-brain barrier. They can also be engineered to carry therapeutic molecules. EVs can be delivered via various routes. The intranasal route is particularly advantageous for delivering them to the central nervous system, making it a promising approach for treating neurological disorders.

This review delves into the promising potential of intranasally administered EVs-based therapies for various medical conditions, with a particular focus on those affecting the brain and central nervous system. Additionally, the potential use of these therapies for pulmonary conditions, cancer, and allergies is examined, offering a hopeful outlook for the future of medical treatments.

The intranasal administration of EVs offers significant advantages over other delivery methods. By directly delivering EVs to the brain, specifically targeting areas that have been injured, this administration proves to be highly efficient and effective, providing reassurance about the progress in medical treatments. Intranasal delivery is not limited to brain-related conditions. It can also benefit other organs like the lungs and stimulate a mucosal immune response against various pathogens due to the highly vascularized nature of the nasal cavity and airways. Moreover, it has the added benefit of minimizing toxicity to non-targeted organs and allows the EVs to remain longer in the body. As a result, there is a growing emphasis on conducting clinical trials for intranasal administration of EVs, particularly in treating respiratory tract pathologies such as coronavirus disease.

Extracellular vesicles (EVs) are lipid-enclosed nanovesicles secreted by diverse cell types that orchestrate intercellular communication through cargo delivery. Their pivotal roles span from supporting the development of normal central nervous system (CNS) to contributing to the pathogenesis of neurological diseases. Particularly noteworthy is their involvement in the propagation of pathogenic proteins, such as those involved in neurodegenerative disorders, and nucleic acids, closely linking them to disease onset and progression. Moreover, EVs have emerged as promising diagnostic biomarkers for neurological disorders and as tools for disease staging, owing to their ability to traverse the blood-brain barrier and their specific, stable, and accessible properties. This review comprehensively explores the realm of CNS-derived EVs found in peripheral blood, encompassing their detection methods, transport mechanisms, and diverse roles in various neurodegenerative diseases. Furthermore, we evaluate the potentials and limitations of EVs in clinical applications and highlight prospective research directions in this rapidly evolving field.

Small extracellular vesicles (sEVs) are particles secreted from cells that play vital roles both in normal physiology and in human disease. sEVs are highly enriched in tetraspanin proteins, such as CD9 and CD63, and contain tetraspanin-enriched membrane microdomains involved in loading of sEVs with macromolecule cargoes and in sEV biogenesis. However, the precise roles of individual tetraspanins in sEV biogenesis and cargo loading remain poorly understood. Here, we report that CD9 negatively regulated CD63 trafficking to tetraspanin-enriched microdomains and its subsequent packaging into sEVs, whereas CD63 had no discernable effect on CD9 localization or packaging. Using super resolution microscopy of individual vesicles, we showed that CD9 governs the fraction of sEVs that are loaded with CD63. Interestingly, CD9-dependent suppression of CD63 packaging was rescued by pharmacological blockade of endocytosis. Together, our data support a model where CD9 contributes to the regulation and secretion of CD63 in an endocytosis-dependent manner to reprogram the contents of sEVs and tetraspanin-enriched microdomains.

Alzheimer's Disease (AD) represents one of the most significant neurodegenerative challenges of our time, with its increasing prevalence and the lack of curative treatments underscoring an urgent need for innovative therapeutic strategies. Stem cells (SCs) therapy emerges as a promising frontier, offering potential mechanisms for neuroregeneration, neuroprotection, and disease modification in AD. This article provides a comprehensive overview of the current landscape and future directions of stem cell therapy in AD treatment, addressing key aspects such as stem cell migration, differentiation, paracrine effects, and mitochondrial translocation. Despite the promising therapeutic mechanisms of SCs, translating these findings into clinical applications faces substantial hurdles, including production scalability, quality control, ethical concerns, immunogenicity, and regulatory challenges. Furthermore, we delve into emerging trends in stem cell modification and application, highlighting the roles of genetic engineering, biomaterials, and advanced delivery systems. Potential solutions to overcome translational barriers are discussed, emphasizing the importance of interdisciplinary collaboration, regulatory harmonization, and adaptive clinical trial designs. The article concludes with reflections on the future of stem cell therapy in AD, balancing optimism with a pragmatic recognition of the challenges ahead. As we navigate these complexities, the ultimate goal remains to translate stem cell research into safe, effective, and accessible treatments for AD, heralding a new era in the fight against this devastating disease.

Neurodegenerative diseases encompass a number of very heterogeneous disorders, primarily characterized by neuronal loss and a concomitant decline in neurological function. Examples of this type of clinical condition are Alzheimer's Disease, Parkinson's Disease, Huntington's Disease and Amyotrophic Lateral Sclerosis. Age has been identified as a major risk in the etiology of these disorders, which explains their increased incidence in developed countries. Unfortunately, despite continued and intensive efforts, no cure has yet been found for any of these diseases; reliable markers that allow for an early diagnosis of the disease and the identification of key molecular events leading to disease onset and progression are lacking. Altered adult neurogenesis appears to precede the appearance of severe symptoms. Given the scarcity of human samples and the considerable differences with model species, increasingly complex human stem-cell-based models are being developed. These are shedding light on the molecular alterations that contribute to disease development, facilitating the identification of new clinical targets and providing a screening platform for the testing of candidate drugs. Moreover, the secretome and other promising features of these cell types are being explored, to use them as replacement cells of high plasticity or as co-adjuvant therapy in combinatorial treatments.

Exosomes, which are small extracellular vesicles (sEVs), serve as versatile regulators of intercellular communication in the progression of various diseases, including neurological disorders. Among the diverse array of cargo they carry, non-coding RNAs (ncRNAs) play key regulatory roles in various pathophysiological processes. Exosomal ncRNAs derived from distinct cells modulate their reciprocal crosstalk locally or remotely, thereby mediating neurological diseases. Nevertheless, the emerging role of exosomal ncRNAsin microglia-mediated phenotypes remains largely unexplored. This review aims to summarise the biological functions of exosomal ncRNAs and the molecular mechanisms that underlie their impact on microglia-mediated intercellular communication, modulating neuroinflammation and synaptic functions within the landscape of neurological disorders. Furthermore, this review comprehensively described the potential applications of exosomal ncRNAs as diagnostic and prognostic biomarkers, as well as innovative therapeutic targets for the treatment of neurological diseases.

Exosomes are a subset of extracellular vesicles (EVs) secreted by nearly all cell types and have emerged as a novel mechanism for intercellular communication within the central nervous system (CNS). These vesicles facilitate the transport of proteins, nucleic acids, lipids, and metabolites between neurons and glial cells, playing a pivotal role in CNS development and the maintenance of homeostasis. Current evidence indicates that exosomes from CNS cells may function as either inhibitors or enhancers in the onset and progression of neurological disorders. Furthermore, exosomes have been found to transport disease-related molecules across the blood-brain barrier, enabling their detection in peripheral blood. This distinctive property positions exosomes as promising diagnostic biomarkers for neurological conditions. Additionally, a growing body of research suggests that exosomes derived from mesenchymal stem cells exhibit reparative effects in the context of neurological disorders. This review provides a concise overview of the functions of exosomes in both physiological and pathological states, with particular emphasis on their emerging roles as potential diagnostic biomarkers and therapeutic agents in the treatment of neurological diseases.

Alzheimer's disease (AD) is a progressive neurodegenerative condition affecting around 50 million people worldwide. Bone marrow-derived mesenchymal stem cells (BMMSCs) have emerged as a promising source for cellular therapy due to their ability to differentiate into multiple cell types and their paracrine effects. However, the direct injection of BMMSCs can lead to potential unpredictable impairments, prompting a renewed interest in their paracrine effects for AD treatment. The specific mechanism and central role of cytokines in this process have not been fully elucidated.

Mouse BMMSCs were isolated, validated, and then transplanted intracerebrally into APP/PS1 female mice. The behavioral tests, including open-field test, novel object recognition test, and Morris water maze were performed, followed by β-amyloidosis plaque and neuron apoptosis analyses. Then the tissue RNA sequencing and mBMMSC cytokine analysis were performed. A cytokine antibody array for BMMSCs and the brain slice models were performed with AD model tissues were used to elucidate the molecular mechanisms. Finally, APP/PS1 mice were administrated with cytokine mixture for cognitive recovery.

Our results demonstrated that BMMSCs significantly improved cognitive function, reduced beta-amyloid plaque deposition, and decreased apoptotic neurons through the activation of the AKT signaling pathway. Using a cytokine antibody array, we identified three highly expressed AKT pathway regulated neuroprotective factors in BMMSCs: IGF1, VEGF, and Periostin2. These cytokines were found to upregulate inhibitors of apoptosis family proteins (IAPs) and suppress Caspase-3 activity in brain slices induced with beta amyloidosis (Aβ), okadaic acid (OA), and lipopolysaccharide (LPS). When injection of this cytokine mixture to APP/PS1 mice also resulted in a mitigation of cognitive impairment.

These findings suggest that the secretory factors IGF1, VEGF, and Periostin2 derived from BMMSCs play a crucial role in neuroprotection by modulating the AKT/IAPs pathway to restore neuronal function. These cytokine sets could be a potential therapeutic strategy for AD and lay the groundwork for promising clinical applications.

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder that is difficult to predict and is typically diagnosed only after symptoms manifest. Recently, CD4+ T cell-derived double-negative T (DNT) cells have shown strong immuno-regulatory properties in both in vitro and in vivo neuronal inflammation studies. However, the effectiveness of DNT cells in treating on AD are not yet fully understood.

This study's aims were three-fold, to (1) evaluate the efficacy of CD4+ T cell-derived DNT cells treatment on AD mice, (2) understand how DNT treatment make changes in different cell types of 5FAD mice, (3) identify the side effects of DNT treatment.

We performed tail vein injection of transformed and amplified CD4+ T cell-derived DNT cells into 5 × FAD mice, while using WT mice and saline injection 5FAD mice as controls. DNT suspensions or NaCl alone were administered to 5 × FAD mice at the 6 months of age. For intravenous injection (n = 10 for both DNT and control injections), 5 × FAD mice were injected with a total of 5 × 106 DNT cells suspended in 200 μL of 0.9% NaCl or 0.9% NaCl alone via the lateral tail vein. Behavioral tests and pathology tests were carried out 30 days after cell transplantation.

Through qualitative analysis, we identified 6 main themes. DNT from young wild-type mice enhance the capability of spatial learning and memory in AD mice. DNT cell treatment rejuvenates the microglial function. DNT cell treatment improves the state of oligodendrocytes. DNT cell treatment finetunes the activation of the immune system. DNT cell treatment improves the synaptic plasticity and increases the complexity of neurons. DNT cell treatment reduces the density of amyloid Beta plaques deposition in the cortex and hippocampus of 5 × FAD mice.

The findings from this study reveal that DNT treatment improved spatial memory and learning abilities, reduced Aβ deposition, and enhanced synaptic plasticity, contrasting with previous reports on thymus-derived DNT cells. Additionally, CD4+ T cell-derived DNT therapy exhibited anti-inflammatory effects and modulated microglial function, promoting a neuroprotective environment. Notably, DNT treatment also reduced tau pathology by decreasing levels of abnormally phosphorylated tau. These findings suggest that CD4+ T cell-derived DNT cells hold therapeutic potential for AD, effectively targeting both Aβ and tau pathologies.

Fragile X Syndrome (FXS) presents with a constellation of phenotypes, including trouble regulating emotion and aggressive behaviors, disordered sleep, intellectual impairments, and atypical physical development. Genetic study of the X chromosome revealed that substantial repeat expansion of the 5' end of the gene fragile X messenger ribonucleoprotein 1 (FMR1) promoted DNA methylation and, consequently, silenced expression of FMR1. Further analysis proved that shorter repeat expansions in FMR1 also manifested in disease at later stages in life. Treatment and therapy options do exist, but they only manage symptoms. Up to now, no cure for FMR1 disorders exists. In this review, we aim to provide an overview of FMR1 biology and the latest research focused on developing therapeutic interventions that can potentially prevent and/or reverse FXS.

Extracellular vesicles (EVs) are heterogeneous entities secreted by cells into their microenvironment and systemic circulation. Circulating EVs carry functional small RNAs and other molecular footprints from their cell of origin, and thus have evident applications in liquid biopsy, therapeutics, and intercellular communication. Yet, the complete transcriptomic landscape of EVs is poorly characterized due to critical limitations including variable protocols used for EV-RNA extraction, quality control, cDNA library preparation, sequencing technologies, and bioinformatic analyses. Consequently, there is a gap in knowledge and the need for a standardized approach in delineating EV-RNAs. Here, we address these gaps by describing the following points by (1) focusing on the large canopy of the EVs and particles (EVPs), which includes, but not limited to - exosomes and other large and small EVs, lipoproteins, exomeres/supermeres, mitochondrial-derived vesicles, RNA binding proteins, and cell-free DNA/RNA/proteins; (2) examining the potential functional roles and biogenesis of EVPs; (3) discussing various transcriptomic methods and technologies used in uncovering the cargoes of EVPs; (4) presenting a comprehensive list of RNA subtypes reported in EVPs; (5) describing different EV-RNA databases and resources specific to EV-RNA species; (6) reviewing established bioinformatics pipelines and novel strategies for reproducible EV transcriptomics analyses; (7) emphasizing the significant need for a gold standard approach in identifying EV-RNAs across studies; (8) and finally, we highlight current challenges, discuss possible solutions, and present recommendations for robust and reproducible analyses of EVP-associated small RNAs. Overall, we seek to provide clarity on the transcriptomics landscape, sequencing technologies, and bioinformatic analyses of EVP-RNAs. Detailed portrayal of the current state of EVP transcriptomics will lead to a better understanding of how the RNA cargo of EVPs can be used in modern and targeted diagnostics and therapeutics. For the inclusion of different particles discussed in this article, we use the terms large/small EVs, non-vesicular extracellular particles (NVEPs), EPs and EVPs as defined in MISEV guidelines by the International Society of Extracellular Vesicles (ISEV).

Retinitis pigmentosa is a neurodegenerative disease with major pathologies of photoreceptor apoptosis and immune imbalance. Mesenchymal stem cells (MSCs) have been approved for clinical application for treating various immune-related or neurodegenerative diseases. The objective of this research was to investigate the mechanisms underlying the safeguarding effects of MSC-derived exosomes in a retinal degenerative disease model.

Interferon gamma-stimulated exosomes (IFNγ-Exos) secreted from MSCs were isolated, purified, and injected into the vitreous body of RCS rats on postnatal day (P) 21. Morphological and functional changes in the retina were examined at P28, P35, P42, and P49 in Royal College of Surgeons (RCS) rats. The mechanism was explored using high-throughput sequencing technology and confirmed in vitro.

Treatment with IFNγ-Exo produced better protective effects on photoreceptors and improved visual function in RCS rats. IFNγ-Exo significantly suppressed the activated microglia and inhibited the inflammatory responses in the retina of RCS rats, which was also confirmed in the lipopolysaccharide-activated microglia cell line BV2. Furthermore, through tRNA-derived small RNA (tsRNA) sequencing, we found that IFNγ-Exos from MSCs contained higher levels of Other-1_17-tRNA-Phe-GAA-1-M3, Other-6_23-tRNA-Lys-TTT-3, and TRF-57:75-GLN-CGG-2-m2 than native exosomes, which mainly regulated inflammatory and immune-related pathways, including the mTOR signaling pathway and EGFR tyrosine kinase inhibitor resistance.

IFNγ stimulation enhanced the neuroprotective effects of MSC-derived exosomes on photoreceptors of the degenerative retina, which may be mediated by immune regulatory tsRNAs acting on microglia. In conclusion, IFNγ-Exo is a promising nanotherapeutic agent for the treatment of retinitis pigmentosa.

Rationale: The level of miR-206-3p in the plasma and temporal cortex is increased in Alzheimer's disease (AD) patients. miR-206-3p antagomir injected into hippocampus ameliorates cognitive deficits by enhancing the level of BDNF. However, the trauma caused by brain injection and susceptibility to degradation limit its application. Methods: To overcome these challenges, we constructed engineered extracellular vesicles derived from mesenchymal stem cell (MSC-EVs) loaded with miR-206-3p antagomir (MSC-EVs-anta) by electroporation technology, and explored the therapeutic effects of MSC-EVs-anta delivered by intranasal administration on AD mice. Transcriptome sequencing and LC-MS/MS proteomic analysis were employed to disclose the mechanism underlying the attenuation of AD phenotypes by MSC-EVs-anta. Results: MSC-EVs-anta had favorable neuroprotection by promoting neurite outgrowth in vitro. Following intranasal administration, MSC-EVs-anta improved learning and memory deficits, promoted hippocampal neurogenesis and synaptic plasticity, and alleviated Aβ deposition. Compared with MSC-EVs or miR-206-3p antagomir alone, MSC-EVs-anta showed superior therapeutic effects. Mechanistically, MSC-EVs-anta significantly upregulated brain-derived neurotrophic factor (BDNF) in AD mice, and activated the BDNF/TrkB signaling pathway. The data from two-omics analyses demonstrated that the differentially expressed proteins and genes significantly regulated by MSC-EVs-anta were primarily enriched in the pathways involved in neurogenesis and synapse. Conclusions: Our findings highlight the intranasal administration of MSC-EVs-anta as a promising strategy for the treatment of AD.

Alzheimer's disease (AD) remains a progressive neurodegenerative disease with no cure. Treatment of AD relies on administering drugs that only subside the symptoms. In recent studies, mesenchymal stem cell (MSC)-exosomes have been marked to possess therapeutic potential for treating AD. This study aims to systematically review and analyse findings that focus on the isolation, characterisation, and sources of MSC-derived exosomes used to unravel the therapeutic potential of these exosomes targeting AD using in vitro and in vivo models. It is hypothesised that MSC-exosomes exhibit high therapeutic potential for AD treatment by exerting various modes of action. PubMed, Scopus, and Medline were used to find relevant published works from January 2016 until December 2020, using assigned keywords including "Alzheimer's disease", "secretome", and "exosomes". Only research articles meeting the predefined inclusion/exclusion criteria were selected and analysed. The risk of bias was assessed using the Office of Health Assessment and Translation tool (OHAT). A total of 17 eligible in vivo and in vitro studies were included in this review. Bone marrow-derived stem cells (BMSCs) were the most used source for exosome isolation, even though studies on exosomes from adipose-derived stem cells (ADSCs) and human umbilical cord stem cells (HUCSCs) provide more information on the characteristics. When the risk of bias was assessed, the studies presented various levels of biases. Notably, the in vitro and in vivo studies revealed neuroprotective properties of MSC-exosomes through different modes of action to alleviate AD pathology. Our review discovered that most MSC exosomes could degrade Aβ plaques, enhance neurogenesis, extenuate neuroinflammatory response through microglial activation, regulate apoptosis and reduce oxidative stress. Delivery of exosomal micro-RNAs was also found to reduce neuroinflammation. Findings from this review provided convincing systematic evidence highlighting the therapeutic properties of MSC-derived exosomes as a prospective source for cell-free (acellular) therapy in treating AD.

Neuroinflammation and the resulting neurodegeneration is a big challenge for the healthcare system, especially with the aging population. Neuroinflammation can result from a variety of insults to the central nervous system leading to an interplay between immune and brain cells that sustains chronic inflammation and injures neural cells. One facilitator of this toxic interplay are exosomes. Exosomes are nano-sized, bilayer lipid vesicles secreted by cells containing proteins, nucleic acids and lipids. Because exosomes can be internalized by other cells, their contents can elicit inflammatory responses and trigger toxicities in recipient cells. On the flip side, exosomes can act as therapeutic vehicles carrying protective cargo to maintain homeostasis. This review discusses exosome biogenesis, composition, and its role in neuroinflammation and neurodegeneration in the context of multiple sclerosis and Alzheimer's disease. The emerging roles of exosomes as biomarkers of neurologic diseases and as therapeutic delivery vehicles are also discussed. With all of these varying roles, interest and excitement in exosomes continue to grow exponentially and their promise as brain therapeutics is only beginning to be explored and harnessed.

The incidence of Alzheimer's disease (AD) has been increasing in recent years as the world's population ages, which poses a significant challenge to public health. Due to the complexity of pathogenesis of AD, currently there is no effective treatment for it. In recent years, cell and gene therapy has attracted widespread attention in the treatment of neurodegenerative diseases. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) represent a novel cell-free therapy with numerous advantages over cell-based therapies owing to their low immunogenicity and high safety profile. We summarize recent progress in the application of EVs for treating AD and the specific mechanisms and outline the underlying mechanisms. We also explore various methods for optimizing the function of MSC-EVs, including gene editing, modifying stem cell culture conditions and peptide modification. In addition, we discuss the therapeutic potentials of MSC-EVs, as well as the obstacles that currently impede their clinical utilization.

Alzheimer's disease (AD) poses a significant public health challenge, increasingly affecting patients' finances, mental health, and functional abilities as the global population ages. Stem cell-derived extracellular vesicles (SC-EVs) have emerged as a promising cell-free therapeutic approach for AD, although their precise mechanisms remain unclear. This meta-analysis aims to evaluate the effectiveness of SC-EVs in treating AD.

We systematically searched PubMed, EMBASE, and Web of Science databases up to December 31, 2023, identifying studies investigating SC-EVs therapy in AD rodent models. Outcome measures included Morris water maze and Y maze tests, β-amyloid pathology, and inflammatory markers. Statistical analyses utilized Stata 15.1 and R software.

This meta-analysis of 16 studies (2017-2023, 314 animals) demonstrates significant efficacy of SC-EVs therapy in AD models. Pooled analyses demonstrated that SC-EVs therapy significantly increased the learning function as measured by Morris water maze tests (MWM) by -1.83 (95% CI = -2.51 to -1.15, p < 0.0001), Y maze test by 1.66 (95% CI = 1.03 to 2.28, p < 0.0001), decreased Aβ plaques in the hippocampal by -2.10 (95% CI = -2.96 to -1.23, p < 0.0001), and proinflammatory cytokines Tumor necrosis factor alpha (TNFα) by -2.61 (95% CI = -4.87 to -0.35, p < 0.05), Interleukin-1 beta (IL-1β) by -2.37 (95% CI = -3.68 to -1.05, p < 0.001).

SC-EVs therapy shows promise in enhancing cognitive function and mitigating AD progression in preclinical models. Future research should focus on standardizing methodologies and comparing SC-EVs isolation techniques and dosing strategies to facilitate clinical translation.

Alzheimer's disease (AD) is the most prevalent kind of dementia and is a long-term degenerative disease. Pathologically, it is defined by the development of extracellular amyloid-β plaques and intracellular neurofibrillary tangles made up of hyperphosphorylated tau protein. This causes neuronal death, particularly in the hippocampus and cortex. Mesenchymal stem cell (MSC)-derived exosomes have been identified as possibly therapeutic and have promise for Alzheimer's disease due to their regenerative characteristics.

A systematic retrieval of information was performed on PubMed. A total of 60 articles were found in a search on mesenchymal stem cells, exosomes, and Alzheimer's disease. A total of 16 ongoing clinical trials were searched and added from clinicaltrials.gov. We added 23 supporting articles to help provide information for certain sections. In total, we included 99 articles in this manuscript: 50 are review articles, 13 are preclinical studies, 16 are clinical studies, 16 are ongoing clinical trials, and 4 are observational studies. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. The clinical trials on mesenchymal stem cell exosomes for Alzheimer's disease were searched on clinicaltrials.gov.

Several experimental investigations have shown that MSC-Exo improves cognitive impairment in rats. In this review paper, we summarized existing understanding regarding the molecular and cellular pathways behind MSC-Exo-based cognitive function restoration, with a focus on MSC-Exo's therapeutic potential in the treatment of Alzheimer's disease.

AD is a significant health issue in our culture and is linked to several important neuropathological characteristics. Exosomes generated from stem cells, such as mesenchymal stem cells (MSCs) or neural stem cells (NSCs), have been examined more and more in a variety of AD models, indicating that they may be viable therapeutic agents for the treatment of diverse disorders. Exosome yields may be increased, and their therapeutic efficacy can be improved using a range of tailored techniques and culture conditions. It is necessary to provide standardized guidelines for exosome manufacture to carry out excellent preclinical and clinical research.

Extracellular vesicles (EV) are a heterogeneous group of lipid particles excreted by cells. They play an important role in regeneration, development, inflammation, and cancer progression, together with the extracellular matrix (ECM), which they constantly interact with. In this review, we discuss direct and indirect interactions of EVs and the ECM and their impact on different physiological processes. The ECM affects the secretion of EVs, and the properties of the ECM and EVs modulate EVs' diffusion and adhesion. On the other hand, EVs can affect the ECM both directly through enzymes and indirectly through the modulation of the ECM synthesis and remodeling by cells. This review emphasizes recently discovered types of EVs bound to the ECM and isolated by enzymatic digestion, including matrix-bound nanovesicles (MBV) and tissue-derived EV (TiEV). In addition to the experimental studies, computer models of the EV-ECM-cell interactions, from all-atom models to quantitative pharmacology models aiming to improve our understanding of the interaction mechanisms, are also considered. STATEMENT OF SIGNIFICANCE: Application of extracellular vesicles in tissue engineering is an actively developing area. Vesicles not only affect cells themselves but also interact with the matrix and change it. The matrix also influences both cells and vesicles. In this review, different possible types of interactions between vesicles, matrix, and cells are discussed. Furthermore, the united EV-ECM system and its regulation through the cellular activity are presented.

Exosomes, as membranous vesicles generated by multiple cell types and secreted to extracellular space, play a crucial role in a range of brain injury-related brain disorders by transporting diverse proteins, RNA, DNA fragments, and other functional substances. The nervous system's pathogenic mechanisms are complicated, involving pathological processes like as inflammation, apoptosis, oxidative stress, and autophagy, all of which result in blood-brain barrier damage, cognitive impairment, and even loss of normal motor function. Exosomes have been linked to the incidence and progression of brain disorders in recent research. As a result, a thorough knowledge of the interaction between exosomes and brain diseases may lead to the development of more effective therapeutic techniques that may be implemented in the clinic. The potential role of exosomes in brain diseases and the crosstalk between exosomes and other pathogenic processes were discussed in this paper. Simultaneously, we noted the delicate events in which exosomes as a media allow the brain to communicate with other tissues and organs in physiology and disease, and compiled a list of natural compounds that modulate exosomes, in order to further improve our understanding of exosomes and propose new ideas for treating brain disorders.

The concept of Yin-Yang, originating in ancient Chinese philosophy, symbolizes two opposing but complementary forces or principles found in all aspects of life. This concept can be quite fitting in the context of extracellular vehicles (EVs) and inflammatory diseases. Over the past decades, numerous studies have revealed that EVs can exhibit dual sides, acting as both pro- and anti-inflammatory agents, akin to the concept of Yin-Yang theory (i.e., two sides of a coin). This has enabled EVs to serve as potential indicators of pathogenesis or be manipulated for therapeutic purposes by influencing immune and inflammatory pathways. This review delves into the recent advances in understanding the Yin-Yang sides of EVs and their regulation in specific inflammatory diseases. We shed light on the current prospects of engineering EVs for treating inflammatory conditions. The Yin-Yang principle of EVs bestows upon them great potential as, therapeutic, and preventive agents for inflammatory diseases.

Alzheimer's disease (AD) is a progressive neurological disorder that primarily impacts cognitive function. Currently there are no disease-modifying treatments to stop or slow its progression. Recent studies have found that several peripheral and systemic abnormalities are associated with AD, and our understanding of how these alterations contribute to AD is becoming more apparent. In this review, we focuse on amyloid‑beta (Aβ), a major hallmark of AD, summarizing recent findings on the source of brain-derived Aβ and discussing where and how the brain-derived Aβ is cleared in vivo. Based on these findings, we propose future strategies for AD prevention and treatment, from a novel perspective on Aβ metabolism.

Multicellular organisms are composed of diverse cell types that must coordinate their behaviors through communication. Cell-cell communication (CCC) is essential for growth, development, differentiation, tissue and organ formation, maintenance, and physiological regulation. Cells communicate through direct contact or at a distance using ligand-receptor interactions. So cellular communication encompasses two essential processes: cell signal conduction for generation and intercellular transmission of signals, and cell signal transduction for reception and procession of signals. Deciphering intercellular communication networks is critical for understanding cell differentiation, development, and metabolism. First, we comprehensively review the historical milestones in CCC studies, followed by a detailed description of the mechanisms of signal molecule transmission and the importance of the main signaling pathways they mediate in maintaining biological functions. Then we systematically introduce a series of human diseases caused by abnormalities in cell communication and their progress in clinical applications. Finally, we summarize various methods for monitoring cell interactions, including cell imaging, proximity-based chemical labeling, mechanical force analysis, downstream analysis strategies, and single-cell technologies. These methods aim to illustrate how biological functions depend on these interactions and the complexity of their regulatory signaling pathways to regulate crucial physiological processes, including tissue homeostasis, cell development, and immune responses in diseases. In addition, this review enhances our understanding of the biological processes that occur after cell-cell binding, highlighting its application in discovering new therapeutic targets and biomarkers related to precision medicine. This collective understanding provides a foundation for developing new targeted drugs and personalized treatments.

Alzheimer's disease (AD) is a neurodegenerative disease that involves multiple systems in the body. Numerous recent studies have revealed bidirectional crosstalk between the brain and bone, but the interaction between bone and brain in AD remains unclear. In this review, we summarize human studies of the association between bone and brain and provide an overview of their interactions and the underlying mechanisms in AD. We review the effects of AD on bone from the aspects of AD pathogenic proteins, AD risk genes, neurohormones, neuropeptides, neurotransmitters, brain-derived extracellular vesicles (EVs), and the autonomic nervous system. Correspondingly, we elucidate the underlying mechanisms of the involvement of bone in the pathogenesis of AD, including bone-derived hormones, bone marrow-derived cells, bone-derived EVs, and inflammation. On the basis of the crosstalk between bone and the brain, we propose potential strategies for the management of AD with the hope of offering novel perspectives on its prevention and treatment. HIGHLIGHTS: The pathogenesis of AD, along with its consequent changes in the brain, may involve disturbing bone homeostasis. Degenerative bone disorders may influence the progression of AD through a series of pathophysiological mechanisms. Therefore, relevant bone intervention strategies may be beneficial for the comprehensive management of AD.

Mesenchymal stem cells (MSCs) reveal multifaceted immunoregulatory properties, which can be applied for diverse refractory and recurrent disease treatment including acute graft-versus-host disease (aGVHD). Distinguishing from MSCs with considerable challenges before clinical application, MSCs-derived exosomes (MSC-Exos) are cell-free microvesicles with therapeutic ingredients and serve as advantageous alternatives for ameliorating the outcomes of aGVHD. MSC-Exos were enriched and identified by western blotting analysis, NanoSight, and transmission electron microscopy (TEM). Bone marrow-derived MSCs (denoted as MSCs) and exosomes (denoted as MSC-Exos) were infused into the aGVHD SD-Wister rat model via tail vein, and variations in general growth and survival of rats were observed. The level of inflammatory factors in serum was quantized by enzyme-linked immunosorbent assay (ELISA). The pathological conditions of the liver and intestine of rats were observed by frozen sectioning. The ratios of CD4+/CD8+ and Treg cell proportions in peripheral blood, together with the autophagy in the spleen and thymus, were analyzed by flow cytometry. After treatment with MSC-Exos, the survival time of aGVHD rats was prolonged, the clinical manifestations of aGVHD in rats were improved, whereas the pathological damage of aGVHD in the liver and intestine was reduced. According to ELISA, we found that MSC-Exos revealed ameliorative effect upon aGVHD inflammation (e.g., TNF-α, IL-2, INF-γ, IL-4, and TGF-β) compared to the MSC group. After MSC-Exo treatment, the ratio of Treg cells in peripheral blood was increased, whereas the ratio of CD4+/CD8+ in peripheral blood and the autophagy in the spleen and thymus was decreased. MSC-Exos effectively suppressed the activation of immune cells and the manifestation of the inflammatory response in the aGVHD rat model. Our data would supply new references for MSC-Exo-based "cell-free" biotherapy for aGVHD in future.

Alzheimer's disease (AD) is the most common type of cognitive impairment. AD is closely related to orthopedic diseases, such as osteoporosis and osteoarthritis, in terms of epidemiology and pathogenesis. Brain and bone tissues can regulate each other in different manners through bone-brain axis. This article reviews the research progress of the relationship between AD and orthopedic diseases, bone-brain axis mechanisms of AD, and AD therapy by targeting bone-brain axis, in order to deepen the understanding of bone-brain communication, promote early diagnosis and explore new therapy for AD patients.

Stem cell therapy holds promise for tissue regeneration, yet significant challenges persist. Emerging as a safer and potentially more effective alternative, extracellular vesicles (EVs) derived from stem cells exhibit remarkable abilities to activate critical signaling cascades, thereby facilitating tissue repair. EVs, nano-scale membrane vesicles, mediate intercellular communication by encapsulating a diverse cargo of proteins, lipids, and nucleic acids. Their therapeutic potential lies in delivering cargos, activating signaling pathways, and efficiently mitigating oxidative stress-an essential aspect of overcoming limitations in stem cell-based tissue repair. This review focuses on engineering and applying EVs in tissue regeneration, emphasizing their role in regulating reactive oxygen species (ROS) pathways. Additionally, we explore strategies to enhance EV therapeutic activity, including functionalization and incorporation of antioxidant defense proteins. Understanding these molecular mechanisms is crucial for optimizing EV-based regenerative therapies. Insights into EV and ROS signaling modulation pave the way for targeted and efficient regenerative therapies harnessing the potential of EVs.

The state of well-being and health of our body is regulated by the fine osmotic and biochemical balance established between the cells of the different tissues, organs, and systems. Specific districts of the human body are defined, kept in the correct state of functioning, and, therefore, protected from exogenous or endogenous insults of both mechanical, physical, and biological nature by the presence of different barrier systems. In addition to the placental barrier, which even acts as a linker between two different organisms, the mother and the fetus, all human body barriers, including the blood-brain barrier (BBB), blood-retinal barrier, blood-nerve barrier, blood-lymph barrier, and blood-cerebrospinal fluid barrier, operate to maintain the physiological homeostasis within tissues and organs. From a pharmaceutical point of view, the most challenging is undoubtedly the BBB, since its presence notably complicates the treatment of brain disorders. BBB action can impair the delivery of chemical drugs and biopharmaceuticals into the brain, reducing their therapeutic efficacy and/or increasing their unwanted bioaccumulation in the surrounding healthy tissues. Recent nanotechnological innovation provides advanced biomaterials and ad hoc customized engineering and functionalization methods able to assist in brain-targeted drug delivery. In this context, lipid nanocarriers, including both synthetic (liposomes, solid lipid nanoparticles, nanoemulsions, nanostructured lipid carriers, niosomes, proniosomes, and cubosomes) and cell-derived ones (extracellular vesicles and cell membrane-derived nanocarriers), are considered one of the most successful brain delivery systems due to their reasonable biocompatibility and ability to cross the BBB. This review aims to provide a complete and up-to-date point of view on the efficacy of the most varied lipid carriers, whether FDA-approved, involved in clinical trials, or used in in vitro or in vivo studies, for the treatment of inflammatory, cancerous, or infectious brain diseases.

Alzheimer's disease (AD) is the most common neurodegenerative illness, characterized by memory loss and cognitive decline, accounting for 60-80% of dementia cases. AD is characterized by senile plaques made up of amyloid β (Aβ) protein, intracellular neurofibrillary tangles caused by hyperphosphorylation of tau protein linked with microtubules, and neuronal loss. Currently, therapeutic treatments and nanotechnological developments are effective in treating the symptoms of AD, but a cure for the illness has not yet been found. Recently, the increased study of extracellular vesicles (EVs) has led to a growing awareness of their significant involvement in neurodegenerative disorders, including AD. Exosomes are small extracellular vesicles that transport various components including messenger RNAs, non-coding RNAs, proteins, lipids, DNA, and other bioactive compounds from one cell to another, facilitating information transmission and material movement. There is growing evidence indicating that exosomes have complex functions in AD. Exosomes may have a dual role in Alzheimer's disease by contributing to neuronal death and also helping to alleviate the pathological progression of the disease. Therefore, the primary aim of this review is to outline the updated understandings on exosomes biogenesis and many functions of exosomes in the generation, conveyance, distribution, and elimination of hazardous proteins related to Alzheimer's disease. This review is intended to provide novel insights for understanding the development, specific treatment, and early detection of Alzheimer's disease.

Alzheimer's disease (AD), a multi-factorial neurodegenerative disorder has affected over 30 million individuals globally and these numbers are expected to increase in the coming decades. Current therapeutic interventions are largely ineffective as they focus on a single target. Development of an effective drug therapy requires a deep understanding of the various factors influencing the onset and progression of the disease. Aging and genetic factors exert a major influence on the development of AD. Other factors like post-viral infections, iron overload, gut dysbiosis, and vascular dysfunction also exacerbate the onset and progression of AD. Further, post-translational modifications in tau, DRP1, CREB, and p65 proteins increase the disease severity through triggering mitochondrial dysfunction, synaptic loss, and differential interaction of amyloid beta with different receptors leading to impaired intracellular signalling. With advancements in neuroscience tools, new inter-relations that aggravate AD are being discovered including pre-existing diseases and exposure to other pathogens. Simultaneously, new therapeutic strategies involving modulation of gene expression through targeted delivery or modulation with light, harnessing the immune response to promote clearance of amyloid deposits, introduction of stem cells and extracellular vesicles to replace the destroyed neurons, exploring new therapeutic molecules from plant, marine and biological sources delivered in the free state or through nanoparticles and use of non-pharmacological interventions like music, transcranial stimulation and yoga. Polypharmacology approaches involving combination of therapeutic agents are also under active investigation for superior therapeutic outcomes. This review elaborates on various disease-causing factors, their underlying mechanisms, the inter-play between different disease-causing players, and emerging therapeutic options including those under clinical trials, for treatment of AD. The challenges involved in AD therapy and the way forward have also been discussed.

Exosomes, lipid bilayer-enclosed small cellular vesicles, are actively secreted by various cells and play crucial roles in intercellular communication. These nanosized vesicles transport internalized proteins, mRNA, miRNA, and other bioactive molecules. Recent findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system disorders. These exosomes exhibit multifaceted properties including anti-apoptotic, anti-inflammatory, neurogenic, and vasculogenic effects. Furthermore, exosomes offer several advantages over stem cell therapy, such as high preservation capacity, low immunogenicity, the ability to traverse the blood-brain barrier, and the potential for drug encapsulation. Consequently, researchers have turned their attention to exosomes as a novel therapeutic avenue. Nonetheless, akin to the limitations of stem cell treatment, the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application. To overcome this hurdle, intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system. By exploiting the olfactory and trigeminal nerve axons, this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier. Notably, exosomes, owing to their small size, can readily access the nerve pathways using this method. As a result, intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosome-based treatments. In this comprehensive review, we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases. Furthermore, we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.

With the increase in the aging population, the occurrence of neurological disorders is rising. Recently, stem cell therapy has garnered attention due to its convenient sourcing, minimal invasiveness, and capacity for directed differentiation. However, there are some disadvantages, such as poor quality control, safety assessments, and ethical and logistical issues. Consequently, scientists have started to shift their attention from stem cells to extracellular vesicles due to their similar structures and properties. Beyond these parallels, extracellular vesicles can enhance biocompatibility, facilitate easy traversal of barriers, and minimize side effects. Furthermore, stem cell-derived extracellular vesicles can be engineered to load drugs and modify surfaces to enhance treatment outcomes. In this review, we summarize the functions of native stem cell-derived extracellular vesicles, subsequently review the strategies for the engineering of stem cell-derived extracellular vesicles and their applications in Alzheimer's disease, Parkinson's disease, and stroke, and discuss the challenges and solutions associated with the clinical translation of stem cell-derived extracellular vesicles.

Alzheimer's disease (AD) is a prevalent form of dementia leading to memory loss, reduced cognitive and linguistic abilities, and decreased self-care. Current AD treatments aim to relieve symptoms and slow disease progression, but a cure is elusive due to limited understanding of the underlying disease mechanisms.

Stem cell technology has the potential to revolutionize AD research. With the ability to self-renew and differentiate into various cell types, stem cells are valuable tools for disease modeling, drug screening, and cell therapy. Recent advances have broadened our understanding beyond the deposition of amyloidβ (Aβ) or tau proteins in AD to encompass risk genes, immune system disorders, and neuron-glia mis-communication, relying heavily on stem cell-derived disease models. These stem cell-based models (e.g., organoids and microfluidic chips) simulate in vivo pathological processes with extraordinary spatial and temporal resolution. Stem cell technologies have the potential to alleviate AD pathology through various pathways, including immunomodulation, replacement of damaged neurons, and neurotrophic support. In recent years, transplantation of glial cells like oligodendrocytes and the infusion of exosomes have become hot research topics.

Although stem cell-based models and therapies for AD face several challenges, such as extended culture time and low differentiation efficiency, they still show considerable potential for AD treatment and are likely to become preferred tools for AD research.