Extracellular vesicle therapeutics in Alzheimer’s disease: mechanisms, progress, and prospects

Yiduo Fang , Xiaotong Hao , Bo Fang

Extracellular Vesicles and Circulating Nucleic Acids ›› 2026, Vol. 7 ›› Issue (1) : 394 -424.

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Extracellular Vesicles and Circulating Nucleic Acids ›› 2026, Vol. 7 ›› Issue (1) :394 -424. DOI: 10.20517/evcna.2025.158
Review
Extracellular vesicle therapeutics in Alzheimer’s disease: mechanisms, progress, and prospects
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Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide, characterized by progressive cognitive decline and a current lack of effective curative treatments. In recent years, extracellular vesicle (EV) therapies have emerged as a cutting-edge approach in AD research due to their unique biological properties. This review systematically examines the role of EVs in the pathogenesis of AD, including their cellular origins and functional attributes. We detail the molecular mechanisms mediated by EVs that influence AD progression and summarize the latest advancements in EV-based therapeutic strategies. Additionally, the review addresses the challenges faced in translating these therapies from bench to bedside, such as standardization, delivery optimization, and safety concerns. Future research directions are discussed to foster the development of innovative and effective treatments for AD. By providing a comprehensive overview, this article aims to lay a theoretical foundation and offer valuable insights for the advancement of novel therapeutic interventions targeting AD.

Keywords

Alzheimer’s disease / extracellular vesicles / mesenchymal stem cells / proteomics / traditional Chinese medicine

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Yiduo Fang, Xiaotong Hao, Bo Fang. Extracellular vesicle therapeutics in Alzheimer’s disease: mechanisms, progress, and prospects. Extracellular Vesicles and Circulating Nucleic Acids, 2026, 7(1): 394-424 DOI:10.20517/evcna.2025.158

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References

[1]

Błaszczyk JW. Pathogenesis of dementia Int J Mol Sci. 2022 24 543 PMC9820433

[2]

Sun C,Sha S,Shan Y.et al. Intranasal delivery of BACE1 siRNA and berberine via engineered stem cell exosomes for the treatment of Alzheimer’s disease Int J Nanomedicine. 2025 20 5873 91 12065464

[3]

Peng L,Bestard-Lorigados I,Song W. The synapse as a treatment avenue for Alzheimer’s Disease Mol Psychiatry. 2022 27 2940 9

[4]

Reiss AB,Glass AD,Wisniewski T.et al. Alzheimer’s disease: many failed trials, so where do we go from here? J Investig Med. 2020;68:1135-40 PMC7872435

[5]

Williams JB,Cao Q,Yan Z. Transcriptomic analysis of human brains with Alzheimer’s disease reveals the altered expression of synaptic genes linked to cognitive deficits Brain Commun. 2021 3 fcab123 PMC8374979

[6]

Zhang R,Song Y,Su X. Necroptosis and Alzheimer’s disease: pathogenic mechanisms and therapeutic opportunities J Alzheimers Dis. 2023 94 S367 86 10473100

[7]

Xie W,Guo D,Li J.et al. CEND1 deficiency induces mitochondrial dysfunction and cognitive impairment in Alzheimer’s disease Cell Death Differ. 2022 29 2417 28 PMC9751129

[8]

Wang C,Zong S,Cui X.et al. The effects of microglia-associated neuroinflammation on Alzheimer’s disease Front Immunol. 2023 14 1117172 PMC9992739

[9]

Morrone CD,Raghuraman R,Hussaini SA,Yu WH. Proteostasis failure exacerbates neuronal circuit dysfunction and sleep impairments in Alzheimer’s disease Mol Neurodegener. 2023 18 27 PMC10119020

[10]

Yang P,Sun F. Aducanumab: the first targeted Alzheimer’s therapy Drug Discov Ther. 2021 15 166 8

[11]

Khan B,Iqbal MK,Khan MA.et al. Unraveling the complexity of Alzheimer’s disease: insights into etiology and advancements in treatment strategies J Mol Neurosci. 2025 75 57

[12]

Wang J,Chen D,Ho EA. Challenges in the development and establishment of exosome-based drug delivery systems J Control Release. 2021 329 894 906

[13]

Alzhrani GN,Alanazi ST,Alsharif SY.et al. Exosomes: isolation, characterization, and biomedical applications Cell Biol Int. 2021 45 1807 31

[14]

Sardar Sinha M,Ansell-Schultz A,Civitelli L.et al. Alzheimer’s disease pathology propagation by exosomes containing toxic amyloid-beta oligomers Acta Neuropathol. 2018 136 41 56 PMC6015111

[15]

Yuyama K,Sun H,Mitsutake S,Igarashi Y. Sphingolipid-modulated exosome secretion promotes clearance of amyloid-β by microglia J Biol Chem. 2012 287 10977 89 3322859

[16]

Li D,Wang Y,Jin X.et al. NK cell-derived exosomes carry miR-207 and alleviate depression-like symptoms in mice J Neuroinflammation. 2020 17 126 PMC7178582

[17]

Kaur S,Verma H,Dhiman M.et al. Brain exosomes: friend or foe in Alzheimer’s Disease? Mol Neurobiol. 2021;58:6610-24

[18]

Chen H,Deng C,Meng Z.et al. Combined catalpol and tetramethylpyrazine promote axonal plasticity in Alzheimer’s disease by inducing astrocytes to secrete exosomes carrying CDK5 mRNA and regulating STAT3 phosphorylation Mol Neurobiol. 2024 61 10770 91

[19]

Cai H,Pang Y,Wang Q.et al. Proteomic profiling of circulating plasma exosomes reveals novel biomarkers of Alzheimer’s disease Alzheimers Res Ther. 2022 14 181 PMC9720984

[20]

McKeever PM,Schneider R,Taghdiri F.et al. MicroRNA expression levels are altered in the cerebrospinal fluid of patients with young-onset Alzheimer’s disease Mol Neurobiol. 2018 55 8826 41 PMC6208843

[21]

Duan L,Ouyang K,Wang J.et al. Exosomes as targeted delivery platform of CRISPR/Cas9 for therapeutic genome editing Chembiochem. 2021 22 3360 8

[22]

Iyaswamy A,Thakur A,Guan XJ.et al. Fe65-engineered neuronal exosomes encapsulating corynoxine-B ameliorate cognition and pathology of Alzheimer’s disease Signal Transduct Target Ther. 2023 8 404 PMC10590775

[23]

Atya HB,Sharaf NM,Abdelghany RM,El-Helaly SN,Taha H. Autophagy and exosomes; inter-connected maestros in Alzheimer’s disease Inflammopharmacology. 2024 32 2061 73 PMC11136856

[24]

Kathait P,Patel PK,Sahu AN. Harnessing exosomes and plant-derived exosomes as nanocarriers for the efficient delivery of plant bioactives Nanomedicine (Lond). 2024 19 2679 97

[25]

Raposo G,Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends J Cell Biol. 2013 200 373 83 PMC3575529

[26]

Suga K,Matsui D,Watanabe N,Okamoto Y,Umakoshi H. Insight into the exosomal membrane: from viewpoints of membrane fluidity and polarity Langmuir. 2021 37 11195 202

[27]

Choi DS,Kim DK,Kim YK,Gho YS. Proteomics, transcriptomics and lipidomics of exosomes and ectosomes Proteomics. 2013 13 1554 71

[28]

Cui Z,Amevor FK,Zhao X.et al. Potential therapeutic effects of milk-derived exosomes on intestinal diseases J Nanobiotechnol. 2023 21 496 PMC10731872

[29]

Hu Q,Su H,Li J.et al. Clinical applications of exosome membrane proteins Precis Clin Med. 2020 3 54 66 PMC7099650

[30]

You Y,Muraoka S,Jedrychowski MP.et al. Human neural cell type-specific extracellular vesicle proteome defines disease-related molecules associated with activated astrocytes in Alzheimer’s disease brain J Extracell Vesicles. 2022 11 e12183 PMC8758831

[31]

Li Y,Hu C,Zhai P.et al. Fibroblastic reticular cell-derived exosomes are a promising therapeutic approach for septic acute kidney injury Kidney Int. 2024 105 508 23

[32]

Liang Y,Duan L,Lu J,Xia J. Engineering exosomes for targeted drug delivery Theranostics. 2021 11 3183 95 PMC7847680

[33]

Verma H,Kaur S,Jeeth P.et al. Understanding Aβ(25-35) peptide altered exosomal proteome and associated pathways linked with the Alzheimer’s disease pathogenesis using human neuroblastoma SH-SY5Y cells Metab Brain Dis. 2024 40 25

[34]

Song Z,Xu Y,Deng W.et al. Brain derived exosomes are a double-edged sword in Alzheimer’s disease Front Mol Neurosci. 2020 13 79 PMC7274346

[35]

Mehrabadi S. Extracellular vesicles: a promising therapeutic approach to Alzheimer’s disease Curr Alzheimer Res. 2024 21 615 24

[36]

Pardridge WM. Blood-brain barrier biology and methodology J Neurovirol. 1999 5 556 69

[37]

Zhao M,Li Q,Chai Y.et al. An anti-CD19-exosome delivery system navigates the blood-brain barrier for targeting of central nervous system lymphoma J Nanobiotechnol. 2025 23 173 PMC11881385

[38]

Kapogiannis D. Exosome biomarkers revolutionize preclinical diagnosis of neurodegenerative diseases and assessment of treatment responses in clinical trials Adv Exp Med Biol. 2020 1195 149

[39]

Kuroda H,Tachikawa M,Yagi Y.et al. Cluster of differentiation 46 is the major receptor in human blood-brain barrier endothelial cells for uptake of exosomes derived from brain-metastatic melanoma cells (SK-Mel-28) Mol Pharm. 2019 16 292 304

[40]

Matsumoto J,Stewart T,Sheng L.et al. Transmission of α-synuclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: another mechanism for initiation and progression of Parkinson's disease? Acta Neuropathol Commun. 2017;5:71 PMC5598000

[41]

Liu B,Su Y,Sun H.et al. Vamp3/syntaxin 4 mediates the basolateral membrane fusion of TfR transcytosis across the BBB and is exploited by pathogenic E. coli Proc Natl Acad Sci U S A. 2025 122 e2500285122 PMC12260585

[42]

Yang T,Martin P,Fogarty B.et al. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio Pharm Res. 2015 32 2003 14 PMC4520542

[43]

Banks WA,Sharma P,Bullock KM,Hansen KM,Ludwig N,Whiteside TL. Transport of extracellular vesicles across the blood-brain barrier: brain pharmacokinetics and effects of inflammation Int J Mol Sci. 2020 21 4407 PMC7352415

[44]

Liang X,Fa W,Wang N.et al. Exosomal miR-532-5p induced by long-term exercise rescues blood-brain barrier function in 5XFAD mice via downregulation of EPHA4 Aging Cell. 2023 22 e13748 PMC9835579

[45]

Kim Y,Lee S,Zhang H.et al. CLEC14A deficiency exacerbates neuronal loss by increasing blood-brain barrier permeability and inflammation J Neuroinflammation. 2020 17 48 PMC7001304

[46]

Beltran-Velasco AI,Clemente-Suárez VJ. Impact of peripheral inflammation on blood-brain barrier dysfunction and its role in neurodegenerative diseases Int J Mol Sci. 2025 26 2440 PMC11942216

[47]

Elashiry M,Carroll A,Yuan J.et al. Oral microbially-induced small extracellular vesicles cross the blood-brain barrier Int J Mol Sci. 2024 25 4509 PMC11049816

[48]

Sandoval H,Ibáñez B,Contreras M.et al. Extracellular vesicles from preeclampsia disrupt the blood-brain barrier by reducing CLDN5 Arterioscler, Thromb, Vasc Biol. 2025 45 298 311

[49]

Zhdanova DY,Poltavtseva RA,Svirshchevskaya EV,Bobkova NV. Effect of intranasal administration of multipotent mesenchymal stromal cell exosomes on memory of mice in Alzheimer’s disease model Bull Exp Biol Med. 2021 170 575 82

[50]

Guo M,Yin Z,Chen F,Lei P. Mesenchymal stem cell-derived exosome: a promising alternative in the therapy of Alzheimer’s disease Alzheimers Res Ther. 2020 12 109 PMC7488700

[51]

Aguiar Koga BA,Fernandes LA,Fratini P,Sogayar MC,Carreira ACO. Role of MSC-derived small extracellular vesicles in tissue repair and regeneration Front Cell Dev Biol. 2022 10 1047094 PMC10014555

[52]

Ma YN,Hu X,Karako K,Song P,Tang W,Xia Y. Exploring the multiple therapeutic mechanisms and challenges of mesenchymal stem cell-derived exosomes in Alzheimer’s disease Biosci Trends. 2024 18 413 30

[53]

Losurdo M,Pedrazzoli M,D’Agostino C.et al. Intranasal delivery of mesenchymal stem cell-derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of Alzheimer’s disease Stem Cells Transl Med. 2020 9 1068 84 PMC7445021

[54]

Liu X,Xia T,Fang Y.et al. Overcoming the blood-brain barrier by using a multistage exosome delivery system to inhibit central nervous system lymphoma Nanomedicine. 2022 41 102523

[55]

Song Y,Liang F,Tian W,Rayhill E,Ye L,Tian X. Optimizing therapeutic outcomes: preconditioning strategies for MSC-derived extracellular vesicles Front Pharmacol. 2025 16 1509418 PMC11847897

[56]

Sha S,Shen X,Cao Y,Qu L. Mesenchymal stem cells-derived extracellular vesicles ameliorate Alzheimer’s disease in rat models via the microRNA-29c-3p/BACE1 axis and the Wnt/β-catenin pathway Aging. 2021 13 15285 306 PMC8221351

[57]

Kaniowska D,Wenk K,Rademacher P.et al. Extracellular vesicles of mesenchymal stromal cells can be taken up by microglial cells and partially prevent the stimulation Induced by β-amyloid Stem Cell Rev Rep. 2022 18 1113 26 PMC8942956

[58]

Ebrahim N,Al Saihati HA,Alali Z.et al. Exploring the molecular mechanisms of MSC-derived exosomes in Alzheimer’s disease: autophagy, insulin and the PI3K/Akt/mTOR signaling pathway Biomed Pharmacother. 2024 176 116836

[59]

Wang ZG,He ZY,Liang S,Yang Q,Cheng P,Chen AM. Comprehensive proteomic analysis of exosomes derived from human bone marrow, adipose tissue, and umbilical cord mesenchymal stem cells Stem Cell Res Ther. 2020 11 511 PMC7694919

[60]

Shin S,Lee J,Kwon Y.et al. Comparative proteomic analysis of the mesenchymal stem cells secretome from adipose, bone marrow, placenta and Wharton’s jelly Int J Mol Sci. 2021 22 845 PMC7829982

[61]

Fiandaca MS,Kapogiannis D,Mapstone M.et al. Identification of preclinical Alzheimer’s disease by a profile of pathogenic proteins in neurally derived blood exosomes: a case-control study Alzheimers Dement. 2015 11 600 7.e1 PMC4329112

[62]

Yakovlev AA. Neuronal exosomes as a new signaling system Biochemistry (Mosc). 2023 88 457 65

[63]

Brás IC,Khani MH,Riedel D.et al. Ectosomes and exosomes modulate neuronal spontaneous activity J Proteomics. 2022 269 104721

[64]

Kronman H,Singh A,Azam S.et al. Multidimensional effects of stress on neuronal exosome levels and simultaneous transcriptomic profiles Biol Psychiatry Glob Open Sci. 2025 5 100401 PMC11667124

[65]

Murai Y,Honda T,Yuyama K.et al. Evaluation of plant ceramide species-induced exosome release from neuronal cells and exosome loading using deuterium chemistry Int J Mol Sci. 2022 23 10751 PMC9505575

[66]

Nogueras-Ortiz CJ,Mahairaki V,Delgado-Peraza F.et al. Astrocyte- and neuron-derived extracellular vesicles from Alzheimer’s disease patients effect complement-mediated neurotoxicity Cells. 2020 9 1618 PMC7407141

[67]

Winston CN,Aulston B,Rockenstein EM.et al. Neuronal exosome-derived human tau is toxic to recipient mouse neurons in vivo J Alzheimers Dis. 2019 67 541 53 PMC8373009

[68]

Goetzl EJ,Mustapic M,Kapogiannis D.et al. Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer’s disease FASEB J. 2016 30 3853 9 PMC5067254

[69]

Xu H,Li H,Zhang P.et al. The functions of exosomes targeting astrocytes and astrocyte-derived exosomes targeting other cell types Neural Regen Res. 2024 19 1947 53 PMC11040311

[70]

Söllvander S,Nikitidou E,Brolin R.et al. Accumulation of amyloid-β by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons Mol Neurodegener. 2016 11 38 PMC4865996

[71]

Gao S,Jia S,Bai L,Li D,Meng C. Transcriptome analysis unveils that exosomes derived from M1-polarized microglia induce ferroptosis of neuronal cells Cells. 2022 11 3956 PMC9776787

[72]

Song Y,Li Z,He T.et al. M2 microglia-derived exosomes protect the mouse brain from ischemia-reperfusion injury via exosomal miR-124 Theranostics. 2019 9 2910 23 PMC6568171

[73]

Frühbeis C,Kuo-Elsner WP,Müller C.et al. Oligodendrocytes support axonal transport and maintenance via exosome secretion PLoS Biol. 2020 18 e3000621 PMC7787684

[74]

Domingues HS,Falcão AM,Mendes-Pinto I,Salgado AJ,Teixeira FG. Exosome circuitry during (De)(Re)myelination of the central nervous system Front Cell Dev Biol. 2020 8 483 PMC7308472

[75]

Du T,Yang CL,Ge MR.et al. M1 Macrophage derived exosomes aggravate experimental autoimmune neuritis via modulating Th1 response Front Immunol. 2020 11 1603 PMC7390899

[76]

Qin J,Yuan H,An X,Liu R,Meng B. Macrophage-derived exosomes exacerbate postoperative cognitive dysfunction in mice through inflammation J Neuroimmunol. 2024 394 578403

[77]

Yuan D,Zhao Y,Banks WA.et al. Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain Biomaterials. 2017 142 1 12 PMC5603188

[78]

Schey KL,Luther JM,Rose KL. Proteomics characterization of exosome cargo Methods. 2015 87 75 82 PMC4591097

[79]

Arioz BI,Tufekci KU,Olcum M.et al. Proteome profiling of neuron-derived exosomes in Alzheimer’s disease reveals hemoglobin as a potential biomarker Neurosci Lett. 2021 755 135914

[80]

Song Z,Xu Y,Zhang L.et al. Comprehensive proteomic profiling of urinary exosomes and identification of potential non-invasive early biomarkers of Alzheimer’s disease in 5XFAD mouse model Front Genet. 2020 11 565479 PMC7674956

[81]

Yuyama K,Sun H,Fujii R,Hemmi I,Ueda K,Igeta Y. Extracellular vesicle proteome unveils cathepsin B connection to Alzheimer’s disease pathogenesis Brain. 2024 147 627 36 PMC10834236

[82]

Verma H,Dhureja M,Yadav A.et al. An in vivo C57BL/6 mouse study demonstrating fine-tuning of serum and brain-derived exosomes reveal therapeutic potential of phytochemical ferulic acid against Alzheimer’s disease Mol Neurobiol. 2025 62 12963 83

[83]

Liang Z,Zhuang H,Cao X,Ma G,Shen L. Subcellular proteomics insights into Alzheimer’s disease development Proteomics Clin Appl. 2024 18 e2200112

[84]

Cano A,Esteban-de-Antonio E,Bernuz M.et al. Plasma extracellular vesicles reveal early molecular differences in amyloid positive patients with early-onset mild cognitive impairment J Nanobiotechnol. 2023 21 54 PMC9930227

[85]

Lee S,Jang KI,Lee H.et al. Multi-proteomic analyses of 5xFAD mice reveal new molecular signatures of early-stage Alzheimer’s disease Aging Cell. 2024 23 e14137 PMC11166370

[86]

Jia L,Zhu M,Kong C.et al. Blood neuro-exosomal synaptic proteins predict Alzheimer’s disease at the asymptomatic stage Alzheimers Dement. 2021 17 49 60 PMC7984076

[87]

Li Y,Xia M,Meng S.et al. MicroRNA-29c-3p in dual-labeled exosome is a potential diagnostic marker of subjective cognitive decline Neurobiol Dis. 2022 171 105800

[88]

Zhou X,Sheikh AM,Matsumoto KI.et al. iTRAQ-based proteomic analysis of APP transgenic mouse urine exosomes Int J Mol Sci. 2022 24 672 PMC9820663

[89]

Soares Martins T,Marçalo R,da Cruz E Silva CB.et al. Novel exosome biomarker candidates for Alzheimer’s disease unravelled through mass spectrometry analysis Mol Neurobiol. 2022 59 2838 54 PMC9016047

[90]

Park J,Lee J,Kim YS,Oh Y. Proteomic profiling of exosomes derived from endometrial stem cells and adipose-derived stem cells Int J Stem Cells. 2026 19 102 12 PMC12954769

[91]

Liu Y,Zhang Z,Ma C,Song J,Hu J,Liu Y. Transplanted MSCs promote alveolar bone repair via hypoxia-induced extracellular vesicle secretion Oral Dis. 2024 30 5221 31 PMC11610711

[92]

Podvin S,Jones A,Liu Q.et al. Mutant presenilin 1 dysregulates exosomal proteome cargo produced by human-induced pluripotent stem cell neurons ACS Omega. 2021 6 13033 56

[93]

Bhavsar PP,Kalita B,Taunk K,Rapole S. Decoding the key hallmarks of chemoresistance: a proteomic tale from breast cancer research Biochim Biophys Acta Rev Cancer. 2025 1880 189404

[94]

Woo HK,Ahn HS,Park J.et al. Size-dependent separation of extracellular vesicle subtypes with exodisc enabling proteomic analysis in prostate cancer J Proteome Res. 2025 24 861 70

[95]

Hakim MA,Sanni A,Osman ST.et al. Serum proteome profiling of diabetic patients treated with DPP4 and SGLT2 inhibitors shows improved cognitive and cardiovascular functions Proteomics. 2025 25 e70000

[96]

Zhang T,Ma S,Lv J.et al. The emerging role of exosomes in Alzheimer’s disease Ageing Res Rev. 2021 68 101321

[97]

Roach JC,Hara J,Fridman D.et al. The coaching for cognition in Alzheimer’s (COCOA) trial: study design Alzheimers Dement (N Y). 2022 8 e12318 PMC9322829

[98]

Roach JC,Rapozo MK,Hara J.et al. ; COCOA Consortium:. A Remotely coached multimodal lifestyle intervention for Alzheimer’s disease ameliorates functional and cognitive outcomes J Alzheimers Dis. 2023 96 591 607

[99]

Liu S,Fan M,Xu JX.et al. Exosomes derived from bone-marrow mesenchymal stem cells alleviate cognitive decline in AD-like mice by improving BDNF-related neuropathology J Neuroinflammation. 2022 19 35 PMC8822863

[100]

Cone AS,Yuan X,Sun L.et al. Mesenchymal stem cell-derived extracellular vesicles ameliorate Alzheimer’s disease-like phenotypes in a preclinical mouse model Theranostics. 2021 11 8129 42 PMC8344012

[101]

Cui GH,Guo HD,Li H.et al. RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of Alzheimer’s disease Immun Ageing. 2019 16 10 PMC6515654

[102]

Chen C,Bao Y,Xing L.et al. Exosomes derived from M2 microglial cells modulated by 1070-nm light improve cognition in an Alzheimer’s disease mouse model Adv Sci (Weinh). 2023 10 e2304025 PMC10646245

[103]

Zhu L,Zhou T,Wu L.et al. Microglial exosome TREM2 ameliorates ferroptosis and neuroinflammation in Alzheimer’s disease by activating the Wnt/β-catenin signaling Sci Rep. 2025 15 24968 PMC12246186

[104]

Xu X,Li J,Wang F.et al. Genetic and pathway complexity in Alzheimer’s disease: Insights from multi-omic data about the immune response and mitochondrial function Neural Regen Res. 2025 Epub ahead of print

[105]

Wang C,Cui C,Xu P.et al. Targeting PDK2 rescues stress-induced impaired brain energy metabolism Mol Psychiatry. 2023 28 4138 50

[106]

Li H,Sun J,Wu Y,Yang Y,Zhang W,Tian Y. Honokiol relieves hippocampal neuronal damage in Alzheimer’s disease by activating the SIRT3-mediated mitochondrial autophagy CNS Neurosci Ther. 2024 30 e14878 PMC11298204

[107]

Reid DM, Barber RC, Thorpe RJ Jr, Sun J, Zhou Z, Phillips NR. Mitochondrial DNA oxidative mutations are elevated in Mexican American women potentially implicating Alzheimer’s disease NPJ Aging. 2022 8 2 PMC9158774

[108]

Wang Z,Wang C,Yuan B.et al. Akkermansia muciniphila and its metabolite propionic acid maintains neuronal mitochondrial division and autophagy homeostasis during Alzheimer’s disease pathologic process via GPR41 and GPR43 Microbiome. 2025 13 16 PMC11744907

[109]

Zhang W,Hong J,Zhang H,Zheng W,Yang Y. Astrocyte-derived exosomes protect hippocampal neurons after traumatic brain injury by suppressing mitochondrial oxidative stress and apoptosis Aging. 2021 13 21642 58 PMC8457605

[110]

Jung YH,Jo HY,Kim DH.et al. Exosome-mediated mitochondrial regulation: a promising therapeutic tool for Alzheimer’s disease and Parkinson’s disease Int J Nanomedicine. 2025 20 4903 17

[111]

Ding YN,Li MQ,Song JY,Guan PP,Wang P. Engineered exosomes improve the effects of curcumin on protecting mitochondria of neurons in Alzheimer’s disease Mater Today Bio. 2025 32 101738 PMC12032918

[112]

Fairley LH,Lai KO,Wong JH.et al. Mitochondrial control of microglial phagocytosis by the translocator protein and hexokinase 2 in Alzheimer’s disease Proc Natl Acad Sci U S A. 2023 120 e2209177120 PMC9974442

[113]

Asiamah EA,Feng B,Guo R.et al. The contributions of the endolysosomal compartment and autophagy to APOEɛ4 allele-mediated increase in Alzheimer’s disease risk J Alzheimers Dis. 2024 97 1007 31

[114]

Nakashima M,Suga N,Fukumoto A,Yoshikawa S,Matsuda S. Exosomes, endosomes, and caveolae as encouraging targets with favorable gut microbiota for the innovative treatment of Alzheimer’s diseases Discov Med. 2024 36 2132 42

[115]

Liu P,Wu A,Li H.et al. Rab21 protein is degraded by both the ubiquitin-proteasome pathway and the autophagy-lysosome pathway Int J Mol Sci. 2022 23 1131 PMC8835697

[116]

Qian J,Ren S,Ren T,Shi R,Qiao L,Kang J. Astrocyte autophagy in neurodegenerative diseases: current progress in mechanisms and therapeutics Neurochem Res. 2025 50 287

[117]

Lin J,Yuan Y,Huang C.et al. TFEB agonist clomiphene citrate activates the autophagy-lysosomal pathway and ameliorates Alzheimer’s disease symptoms in mice J Biol Chem. 2024 300 107929 PMC11599454

[118]

Rai SN,Tiwari N,Singh P.et al. Therapeutic potential of vital transcription factors in Alzheimer’s and Parkinson’s disease with particular emphasis on transcription factor EB mediated autophagy Front Neurosci. 2021 15 777347 PMC8712758

[119]

Liu H,Li C,Zhang X.et al. BMSC-Exosomes attenuate ALP dysfunction by restoring lysosomal function via the mTOR/TFEB Axis to reduce cerebral ischemia-reperfusion injury Exp Neurol. 2024 376 114726

[120]

Zhang S,Qiu Y,Feng Y.et al. Calpain-2 facilitates autophagic/lysosomal defects and apoptosis in ARPE-19 cells and rats induced by exosomes from RPE cells under NaIO3 stimulation Oxid Med Cell Longev. 2023 2023 3310621 PMC9873447

[121]

Cazzaro S,Fang C,Khan H.et al. Slingshot homolog-1 mediates the secretion of small extracellular vesicles containing misfolded proteins by regulating autophagy cargo receptors and actin dynamics Front Aging Neurosci. 2022 14 933979 PMC9452914

[122]

Kim SJ,Russell AE,Wang W.et al. miR-146a Dysregulates energy metabolism during neuroinflammation J Neuroimmune Pharmacol. 2022 17 228 41 PMC8611101

[123]

Han J,Zhang X,Kang L,Guan J. Extracellular vesicles as therapeutic modulators of neuroinflammation in Alzheimer’s disease: a focus on signaling mechanisms J Neuroinflammation. 2025 22 120 PMC12023694

[124]

Xie HM,Su X,Zhang FY.et al. Profile of the RNA in exosomes from astrocytes and microglia using deep sequencing: implications for neurodegeneration mechanisms Neural Regen Res. 2022 17 608 17 PMC8504369

[125]

Ye Y,Gao M,Shi W.et al. The immunomodulatory effects of mesenchymal stem cell-derived extracellular vesicles in Alzheimer’s disease Front Immunol. 2023 14 1325530 PMC10800421

[126]

Park AM,Tsunoda I. Helicobacter pylori infection in the stomach induces neuroinflammation: the potential roles of bacterial outer membrane vesicles in an animal model of Alzheimer’s disease Inflamm Regen. 2022 42 39 PMC9442937

[127]

Liu WL,Lin HW,Lin MR.et al. Emerging blood exosome-based biomarkers for preclinical and clinical Alzheimer’s disease: a meta-analysis and systematic review Neural Regen Res. 2022 17 2381 90 PMC9120706

[128]

Kalluri VS,Smaglo BG,Mahadevan KK.et al. Engineered exosomes with Kras(G12D) specific siRNA in pancreatic cancer: a phase I study with immunological correlates Nat Commun. 2025 16 8696 PMC12485160

[129]

Li M,Huang H,Wei X.et al. Correction: clinical investigation on nebulized human umbilical cord MSC-derived extracellular vesicles for pulmonary fibrosis treatment Signal Transduct Target Ther. 2025 10 235 PMC12271339

[130]

Xie X,Song Q,Dai C.et al. Clinical safety and efficacy of allogenic human adipose mesenchymal stromal cells-derived exosomes in patients with mild to moderate Alzheimer’s disease: a phase I/II clinical trial Gen Psychiatr. 2023 36 e101143 PMC10582850

[131]

Ramon J,Pinheiro C,Vandendriessche C.et al. Pre-formation loading of extracellular vesicles with exogenous molecules using photoporation J Nanobiotechnol. 2025 23 556 PMC12333136

[132]

Obuchi W,Zargani-Piccardi A,Leandro K.et al. Engineering of CD63 enables selective extracellular vesicle cargo loading and enhanced payload delivery J Extracell Vesicles. 2025 14 e70094 PMC12173531

[133]

Huang K,Garimella S,Clay-Gilmour A.et al. Comparison of human urinary exosomes isolated via ultracentrifugation alone versus ultracentrifugation followed by SEC Column-purification J Pers Med. 2022 12 340 PMC8950278

[134]

Kluszczyńska K, Pęczek Ł, Różański A, Czernek L, Duechler M. U6/miR-211 expression ratio as a purity parameter for HEK293 cell-derived exosomes Acta Biochim Pol. 2022 69 409 15

[135]

Jiang Z,Liu G,Li J. Recent progress on the isolation and detection methods of exosomes Chem Asian J. 2020 15 3973 82

[136]

Zarovni N,Corrado A,Guazzi P.et al. Integrated isolation and quantitative analysis of exosome shuttled proteins and nucleic acids using immunocapture approaches Methods. 2015 87 46 58

[137]

An M,Wu J,Zhu J,Lubman DM. Comparison of an optimized ultracentrifugation method versus size-exclusion chromatography for isolation of exosomes from human serum J Proteome Res. 2018 17 3599 605 PMC6292670

[138]

Sidhom K,Obi PO,Saleem A. A review of exosomal isolation methods: is size exclusion chromatography the best option? Int J Mol Sci. 2020;21:6466 PMC7556044

[139]

Brown PN,Yin H. Polymer-based purification of extracellular vesicles Methods Mol Biol. 2017 1660 91 103

[140]

Huang LH,Rau CS,Wu SC.et al. Identification and characterization of hADSC-derived exosome proteins from different isolation methods J Cell Mol Med. 2021 25 7436 50 PMC8335681

[141]

Kurian TK,Banik S,Gopal D,Chakrabarti S,Mazumder N. Elucidating methods for isolation and quantification of exosomes: a review Mol Biotechnol. 2021 63 249 66 PMC7940341

[142]

Abaidullah N,Muhammad K,Waheed Y. Delving into nanoparticle systems for enhanced drug delivery technologies AAPS PharmSciTech. 2025 26 74

[143]

Zhou C,Zhang B,Yang Y.et al. Stem cell-derived exosomes: emerging therapeutic opportunities for wound healing Stem Cell Res Ther. 2023 14 107 PMC10134577

[144]

Dairov A,Issabekova A,Sarsenova M.et al. Study of the Therapeutic effect of cytokine-preconditioned mesenchymal stem cells and their exosomes in a mouse model of psoriasis Biology (Basel). 2025 14 1033 PMC12383953

[145]

Kwon HH,Yang SH,Lee J.et al. Combination treatment with human adipose tissue stem cell-derived exosomes and fractional CO2 laser for acne scars: a 12-week prospective, double-blind, randomized, split-face study Acta Derm Venereol. 2020 100 adv00310 PMC9309822

[146]

Catitti G,Cufaro MC,De Bellis D.et al. Extracellular vesicles in regenerative processes associated with muscle injury recovery of professional athletes undergoing sub maximal strength rehabilitation Int J Mol Sci. 2022 23 14913 PMC9739739

[147]

Bu Z,Jing J,Liu W.et al. Treatment of denervated muscle atrophy by injectable dual-responsive hydrogels loaded with extracellular vesicles Adv Sci (Weinh). 2025 12 e2412248

[148]

Lu X,Xu R,Dong X.et al. Cell-derived exosome therapy for diabetic peripheral neuropathy: a preclinical animal studies systematic review and meta-analysis Stem Cell Res Ther. 2025 16 297 PMC12150502

[149]

Lee JY,Kim J,Na K,Ahn HJ. GMP manufacturing of umbilical cord blood mesenchymal stem cell-released exosomes and verification of wound healing efficacy Nanotheranostics. 2025 9 95 109 PMC11980038

[150]

Whitford W,Guterstam P. Exosome manufacturing status Future Med Chem. 2019 11 1225 36

[151]

Li J,Lee Y,Johansson HJ.et al. Serum-free culture alters the quantity and protein composition of neuroblastoma-derived extracellular vesicles J Extracell Vesicles. 2015 4 26883 PMC4447833

[152]

Duan L,Li X,Xu X.et al. Large-scale preparation of synovial fluid mesenchymal stem cell-derived exosomes by 3D bioreactor culture. J Vis Exp. 2022

[153]

Lin B,Lei Y,Wang J.et al. Microfluidic-based exosome analysis for liquid biopsy Small Methods. 2021 5 e2001131

[154]

Zhang W,Lu R,Zhang L. Preparation of dual-functional composite magnetic nanomaterials modified with different metals/aptamers and their performance in exosome enrichment Se Pu. 2021 39 1128 36

[155]

Lee JH,Ha DH,Go HK.et al. Reproducible large-scale isolation of exosomes from adipose tissue-derived mesenchymal stem/stromal cells and their application in acute kidney injury Int J Mol Sci. 2020 21 4774 PMC7370182

[156]

Ulpiano C,Salvador W,Franchi-Mendes T.et al. Continuous collection of human mesenchymal-stromal-cell-derived extracellular vesicles from a stirred tank reactor operated under xenogeneic-free conditions for therapeutic applications Stem Cell Res Ther. 2025 16 210 PMC12023423

[157]

Ma CY,Zhai Y,Li CT.et al. Translating mesenchymal stem cell and their exosome research into GMP compliant advanced therapy products: promises, problems and prospects Med Res Rev. 2024 44 919 38

[158]

Shahlaei M,Afkhami H,Ahmadieh-Yazdi A.et al. Corrigendum to “Exosomes in Alzheimer’s disease: from pathogenesis to therapeutics - a comprehensive review of diagnostic and drug delivery applications” [Biomed. Pharmacother. 192 (2025) 118548] Biomed Pharmacother. 2025 192 118632

[159]

Ebadpour N,Abavisani M,Karav S,Kesharwani P,Sahebkar A. Exosome/Extracellular vesicles-based therapeutics in Alzheimer’s disease: neuroprotective roles and future perspectives J Mol Neurosci. 2025 75 137

[160]

Chen YS,Lin EY,Chiou TW,Harn HJ. Exosomes in clinical trial and their production in compliance with good manufacturing practice Tzu Chi Med J. 2020 32 113 20 PMC7137364

[161]

Gurriaran-Rodriguez U,De Repentigny Y,Kothary R,Rudnicki MA. Isolation of small extracellular vesicles from regenerating muscle tissue using tangential flow filtration and size exclusion chromatography Skelet Muscle. 2024 14 22 PMC11468478

[162]

Gelibter S,Marostica G,Mandelli A.et al. The impact of storage on extracellular vesicles: A systematic study J Extracell Vesicles. 2022 11 e12162 PMC8804350

[163]

Lu L,Han C,Wang M.et al. Assessment of bovine milk exosome preparation and lyophilized powder stability J Extracell Biol. 2024 3 e70009 PMC11565256

[164]

Budgude P,Kale V,Vaidya A. Cryopreservation of mesenchymal stromal cell-derived extracellular vesicles using trehalose maintains their ability to expand hematopoietic stem cells in vitro Cryobiology. 2021 98 152 63

[165]

Wang CK,Tsai TH,Lee CH. Regulation of exosomes as biologic medicines: Regulatory challenges faced in exosome development and manufacturing processes Clin Transl Sci. 2024 17 e13904 PMC11307316

[166]

Huang Q,Wang S,Liu Z,Rao L,Cheng K,Mao X. Engineering exosomes for targeted neurodegenerative therapy: innovations in biogenesis, drug loading, and clinical translation Theranostics. 2026 16 545 79 PMC12665144

[167]

Li Q,Li Y,Shao J.et al. Exploring regulatory frameworks for exosome therapy: insights and perspectives Health Care Sci. 2025 4 299 309 PMC12371722

[168]

Ansarian MA,Fatahichegeni M,Wang Y,Ren J,Zhang T,Wang X. Exosomal biomarkers in leukemia: translational potential and regulatory challenges for precision medicine applications Front Immunol. 2025 16 1677088 PMC12521259

[169]

Azuma K,Yamanaka S. Recent policies that support clinical application of induced pluripotent stem cell-based regenerative therapies Regen Ther. 2016 4 36 47 PMC6581825

[170]

Sanborn V,Drake JD,Alaimo H.et al. Investigating salivary extracellular vesicles as biomarkers for Alzheimer’s disease: ExosomeAD study design and baseline characteristics Alzheimers Dement. 2026 21 Suppl e105183 PMC12788618

[171]

Van Delen M,Derdelinckx J,Wouters K,Nelissen I,Cools N. A systematic review and meta-analysis of clinical trials assessing safety and efficacy of human extracellular vesicle-based therapy J Extracell Vesicles. 2024 13 e12458 PMC11220457

[172]

Yang Y,Wang F,Li Y.et al. Engineered extracellular vesicles with polypeptide for targeted delivery of doxorubicin against EGFR‑positive tumors Oncol Rep. 2024 52 154 PMC11465103

[173]

Sun D,Zhuang X,Xiang X.et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes Mol Ther. 2010 18 1606 14 PMC2956928

[174]

Gong L,Chen Z,Feng K.et al. A versatile engineered extracellular vesicle platform simultaneously targeting and eliminating senescent stromal cells and tumor cells to promote tumor regression J Nanobiotechnol. 2024 22 105 PMC10926582

[175]

Kim HK,Choi Y,Kim KH.et al. Scalable production of siRNA-encapsulated extracellular vesicles for the inhibition of KRAS-mutant cancer using acoustic shock waves J Extracell Vesicles. 2024 13 e12508 PMC11424982

[176]

Pham TC,Jayasinghe MK,Pham TT.et al. Covalent conjugation of extracellular vesicles with peptides and nanobodies for targeted therapeutic delivery J Extracell Vesicles. 2021 10 e12057 PMC7886705

[177]

Gu Y,Li A,Zeng Y.et al. Engineering hybrid nanoparticles for targeted codelivery of triptolide and CYP3A4-siRNA against pulmonary metastatic melanoma Sci Adv. 2025 11 eadv6990 PMC12285696

[178]

Zhu Z,Zhai Y,Hao Y.et al. Specific anti-glioma targeted-delivery strategy of engineered small extracellular vesicles dual-functionalised by Angiopep-2 and TAT peptides J Extracell Vesicles. 2022 11 e12255 PMC9451528

[179]

Li B,Chen X,Qiu W.et al. Synchronous disintegration of ferroptosis defense axis via engineered exosome-conjugated magnetic nanoparticles for glioblastoma therapy Adv Sci (Weinh). 2022 9 e2105451 PMC9189685

[180]

Zhang H,Feng K,Han M.et al. Homologous magnetic targeted immune vesicles for amplifying immunotherapy via ferroptosis activation augmented photodynamic therapy against glioblastoma J Control Release. 2025 383 113816

[181]

Lin EY,Hsu SX,Wu BH.et al. Engineered exosomes containing microRNA-29b-2 and targeting the somatostatin receptor reduce presenilin 1 expression and decrease the β-amyloid accumulation in the brains of mice with Alzheimer’s disease Int J Nanomedicine. 2024 19 4977 94

[182]

Wang Y,Huo Y,Zhao C.et al. Engineered exosomes with enhanced stability and delivery efficiency for glioblastoma therapy J Control Release. 2024 368 170 83

[183]

Yang J,Li Y,Jiang S.et al. Engineered brain-targeting exosome for reprogramming immunosuppressive microenvironment of glioblastoma Exploration (Beijing). 2025 5 20240039 PMC12087404

[184]

Hua D,Tang L,Wang W.et al. Improved antiglioblastoma activity and BBB permeability by conjugation of paclitaxel to a cell-penetrative MMP-2-cleavable peptide Adv Sci (Weinh). 2021 8 2001960 PMC7856885

[185]

Ma M,Wang J,Zhong W,Li Z,Zhao Y. Cleavable antibody-conjugated Aβ specific immune exosome for combination Alzheimer’s disease immunotherapy Angew Chem Int Ed Engl. 2025 64 e202517917

[186]

Li M,Lu L,Bao Q.et al. Radiotherapy-derived engineered stem cell exosomes improve anti-glioma immunotherapy by promoting the formation of tertiary lymphoid structure and improve the release of type I interferon J Nanobiotechnol. 2025 23 239 PMC11929319

[187]

Tian T,Liang R,Erel-Akbaba G.et al. Immune checkpoint inhibition in GBM primed with radiation by engineered extracellular vesicles ACS Nano. 2022 16 1940 53 PMC9020451

[188]

Dong Z,Yin T,Deng Z.et al. Hybridoma-inspired strategy crafts tailored multifunctional exosomes for precision therapy Proc Natl Acad Sci U S A. 2025 122 e2424547122 PMC12452929

[189]

Du B,Zou Q,Wang X.et al. Multi-targeted engineered hybrid exosomes as Aβ nanoscavengers and inflammatory modulators for multi-pathway intervention in Alzheimer’s disease Biomaterials. 2025 322 123403

[190]

Han J,Sul JH,Lee J.et al. Engineered exosomes with a photoinducible protein delivery system enable CRISPR-Cas-based epigenome editing in Alzheimer’s disease Sci Transl Med. 2024 16 eadi4830

[191]

Liu H,Jin M,Ji M,Zhang W,Liu A,Wang T. Hypoxic pretreatment of adipose-derived stem cell exosomes improved cognition by delivery of circ-Epc1 and shifting microglial M1/M2 polarization in an Alzheimer’s disease mice model Aging. 2022 14 3070 83 PMC9037259

[192]

Huber CC,Callegari EA,Paez MD,Romanova S,Wang H. Heat shock-induced extracellular vesicles derived from neural stem cells confer marked neuroprotection against oxidative stress and amyloid-β-caused neurotoxicity Mol Neurobiol. 2022 59 7404 12 PMC10088367

[193]

Xu Y,Dong Y,Wang C,Jiang Q,Chu H,Tian Y. Lovastatin attenuates sevoflurane-induced cognitive disorder in aged rats via reducing Aβ accumulation Neurochem Int. 2021 148 105078

[194]

Liang J,Zhao J,Yang L.et al. MSC-exosomes pretreated by Danshensu extracts pretreating to target the hsa-miR-27a-5p and STAT3-SHANK2 to enhanced antifibrotic therapy Stem Cell Res Ther. 2025 16 40 PMC11792327

[195]

Chen L,Zhang J,Yu J,Guo S,Tian W. LPS pretreated dental follicle stem cell derived exosomes promote periodontal tissue regeneration via miR-184 and PPARα-Akt-JNK signaling pathway Stem Cell Res Ther. 2025 16 347 PMC12224499

[196]

Olson C,Ivanov K,Boyes D.et al. Dual-omics approach unveils novel perspective on the quality control of genetically engineered exosomes Pharmaceutics. 2024 16 824 PMC11207238

[197]

Long R,Wang S. Exosomes from preconditioned mesenchymal stem cells: Tissue repair and regeneration Regen Ther. 2024 25 355 66 PMC10875222

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