Extracellular vesicles in bone aging: therapeutic strategies and applications

Abstract

As global aging intensifies, the issue of bone aging has become increasingly prominent. Osteoporosis and osteoarthritis, which are common complications of bone aging, significantly impair patients’ quality of life due to their high prevalence and disability rates, thereby presenting a major public health challenge. Extracellular vesicles (EVs), nanoscale particles released by cells, are regarded as an ideal platform for bone aging due to their high biocompatibility, ease of modification, and significant therapeutic efficacy. This review provides a comprehensive summary of the latest advancements in mammalian-, bacterial-, and plant-derived EVs, particularly in the context of bone aging. Furthermore, organoids, as lab-grown models replicating organ physiology, produce organoid-derived EVs that represent an especially promising avenue for therapeutic application. This review focuses on exploring potential therapeutic strategies that capitalize on the unique advantages of each EV type for treating bone aging. It is anticipated that a thorough comprehension of these EV types will unveil new avenues for bone aging treatment.

Keywords

Extracellular vesicle / bone aging / osteoporosis / osteoarthritis / engineering modification

References

[1] Fang H,Liu J,Deng Z.The mechanism of bone remodeling after bone aging.Clin Interv Aging2022;17:405-15 PMCID:PMC8994557

[2] Chandra A.Skeletal aging and osteoporosis: mechanisms and therapeutics.Int J Mol Sci2021;22:3553 PMCID:PMC8037620

[3] Cui J,Zhu T,Zhang J.Osteocytes in bone aging: advances, challenges, and future perspectives.Ageing Res Rev2022;77:101608

[4] Viganò M,Listorti E.Proximal hip fractures in 71,920 elderly patients: incidence, epidemiology, mortality and costs from a retrospective observational study.BMC Public Health2023;23:1963 PMCID:PMC10566057

[5] Song S,Yang Y.Advances in pathogenesis and therapeutic strategies for osteoporosis.Pharmacol Ther2022;237:108168

[6] Hu Y,Zhi X.RANKL from bone marrow adipose lineage cells promotes osteoclast formation and bone loss.EMBO Rep2021;22:e52481 PMCID:PMC8406405

[7] Witwer KW,O'Driscoll L.Updating MISEV: evolving the minimal requirements for studies of extracellular vesicles.J Extracell Vesicles2021;10:e12182 PMCID:PMC8710080

[8] O’Brien K,Ughetto S,Breakefield XO.RNA delivery by extracellular vesicles in mammalian cells and its applications.Nat Rev Mol Cell Biol2020;21:585-606 PMCID:PMC7249041

[9] Herrmann IK,Fuhrmann G.Extracellular vesicles as a next-generation drug delivery platform.Nat Nanotechnol2021;16:748-59

[10] Rachner TD,Hofbauer LC.Osteoporosis: now and the future.Lancet2011;377:1276-87 PMCID:PMC3555696

[11] Robbins PD.Regulation of immune responses by extracellular vesicles.Nat Rev Immunol2014;14:195-208 PMCID:PMC4350779

[12] Zhang T,Lv J.The emerging role of exosomes in Alzheimer’s disease.Ageing Res Rev2021;68:101321

[13] Chronopoulos A.Emerging role of bacterial extracellular vesicles in cancer.Oncogene2020;39:6951-60 PMCID:PMC7557313

[14] Théry C,Aikawa E.Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines.J Extracell Vesicles2018;7:1535750 PMCID:PMC6322352

[15] Witwer KW.Extracellular vesicles or exosomes?.J Extracell Vesicles2019;8:1648167 PMCID:PMC6711079

[16] Fonseka P,Mathivanan S.Introduction to the community of extracellular vesicles.Subcell Biochem2021;97:3-18

[17] Sharma S,Kaneti YV.Extracellular vesicle nanoarchitectonics for novel drug delivery applications.Small2021;17:e2102220

[18] Mathieu M,Lavieu G.Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication.Nat Cell Biol2019;21:9-17

[19] Colombo M,Théry C.Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles.Annu Rev Cell Dev Biol2014;30:255-89

[20] Kowal J,Colombo M.Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes.Proc Natl Acad Sci U S A2016;113:E968-77 PMCID:PMC4776515

[21] Kowal J,Théry C.Biogenesis and secretion of exosomes.Curr Opin Cell Biol2014;29:116-25

[22] Liu DA,Wu B.A phosphoinositide switch mediates exocyst recruitment to multivesicular endosomes for exosome secretion.Nat Commun2023;14:6883 PMCID:PMC10613218

[23] Schwechheimer C.Outer-membrane vesicles from Gram-negative bacteria: biogenesis and functions.Nat Rev Microbiol2015;13:605-19 PMCID:PMC5308417

[24] Lee EY,Kim DK.Gram-positive bacteria produce membrane vesicles: proteomics-based characterization of Staphylococcus aureus-derived membrane vesicles.Proteomics2009;9:5425-36

[25] Schrempf H,Walter S,Meschke H.Extracellular Streptomyces vesicles: amphorae for survival and defence.Microb Biotechnol2011;4:286-99 PMCID:PMC3818868

[26] Brown L,Cabezas-Sanchez P,Casadevall A.Extracellular vesicles produced by the Gram-positive bacterium Bacillus subtilis are disrupted by the lipopeptide surfactin.Mol Microbiol2014;93:183-98 PMCID:PMC4079059

[27] Albuquerque PC,Rodrigues ML.Vesicular transport in Histoplasma capsulatum: an effective mechanism for trans-cell wall transfer of proteins and lipids in ascomycetes.Cell Microbiol2008;10:1695-710 PMCID:PMC2562661

[28] Vallejo MC,Longo LV.Lipidomic analysis of extracellular vesicles from the pathogenic phase of Paracoccidioides brasiliensis.PLoS One2012;7:e39463 PMCID:PMC3382159

[29] Rodrigues ML,Oliveira DL.Extracellular vesicles produced by Cryptococcus neoformans contain protein components associated with virulence.Eukaryot Cell2008;7:58-67 PMCID:PMC2224146

[30] Toyofuku M,Eberl L.Types and origins of bacterial membrane vesicles.Nat Rev Microbiol2019;17:13-24

[31] Burdett ID.Electron microscope study of septum formation in Escherichia coli strains B and B-r during synchronous growth.J Bacteriol1974;119:1039-56 PMCID:PMC245711

[32] Kadurugamuwa JL,Beveridge TJ.Surface action of gentamicin on Pseudomonas aeruginosa.J Bacteriol1993;175:5798-805 PMCID:PMC206658

[33] Roier S,Cakar F.A novel mechanism for the biogenesis of outer membrane vesicles in Gram-negative bacteria.Nat Commun2016;7:10515

[34] Turnbull L,Hynen AL.Explosive cell lysis as a mechanism for the biogenesis of bacterial membrane vesicles and biofilms.Nat Commun2016;7:11220 PMCID:PMC4834629

[35] Bauwens A,Karch H,Bielaszewska M.Antibiotic-mediated modulations of outer membrane vesicles in Enterohemorrhagic Escherichia coli O104:H4 and O157:H7.Antimicrob Agents Chemother2017;61 PMCID:PMC5571282

[36] Cui Y,He Y.Plant extracellular vesicles.Protoplasma2020;257:3-12

[37] Wang J,Wang J.EXPO, an exocyst-positive organelle distinct from multivesicular endosomes and autophagosomes, mediates cytosol to cell wall exocytosis in Arabidopsis and tobacco cells.Plant Cell2010;22:4009-30 PMCID:PMC3027174

[38] Hatsugai N,Tamura K.A novel membrane fusion-mediated plant immunity against bacterial pathogens.Genes Dev2009;23:2496-506 PMCID:PMC2779742

[39] Halperin W.Ultrastructural changes during growth and embryogenesis in carrot cell cultures.J Ultrastruct Res1967;18:428-43

[40] An Q,Hückelhoven R.Do plant cells secrete exosomes derived from multivesicular bodies?.Plant Signal Behav2007;2:4-7 PMCID:PMC2633885

[41] Liu H,Su J.Engineered mammalian and bacterial extracellular vesicles as promising nanocarriers for targeted therapy.Extracell Vesicles Circ Nucl Acids2022;3:63-86 PMCID:PMC11648430

[42] Abels ER.Introduction to extracellular vesicles: biogenesis, rna cargo selection, content, release, and uptake.Cell Mol Neurobiol2016;36:301-12 PMCID:PMC5546313

[43] Trajkovic K,Chiantia S.Ceramide triggers budding of exosome vesicles into multivesicular endosomes.Science2008;319:1244-7

[44] Raposo G.Extracellular vesicles: exosomes, microvesicles, and friends.J Cell Biol2013;200:373-83 PMCID:PMC3575529

[45] Shockman GD.Structure, function, and assembly of cell walls of gram-positive bacteria.Annu Rev Microbiol1983;37:501-27

[46] Jiang Y,Roland KL.Membrane vesicles of Clostridium perfringens type A strains induce innate and adaptive immunity.Int J Med Microbiol2014;304:431-43 PMCID:PMC4285460

[47] Rivera J,Nakouzi AS,Nicola A.Bacillus anthracis produces membrane-derived vesicles containing biologically active toxins.Proc Natl Acad Sci U S A2010;107:19002-7 PMCID:PMC2973860

[48] Olaya-Abril A,McConnell MJ.Characterization of protective extracellular membrane-derived vesicles produced by Streptococcus pneumoniae.J Proteomics2014;106:46-60

[49] Lee JH,Lee T,Lee JC.Transcription factor σ^B plays an important role in the production of extracellular membrane-derived vesicles in Listeria monocytogenes.PLoS One2013;8:e73196 PMCID:PMC3748028

[50] Brown L,Prados-Rosales R.Through the wall: extracellular vesicles in Gram-positive bacteria, mycobacteria and fungi.Nat Rev Microbiol2015;13:620-30 PMCID:PMC4860279

[51] Silhavy TJ,Walker S.The bacterial cell envelope.Cold Spring Harb Perspect Biol2010;2:a000414 PMCID:PMC2857177

[52] Kojer K.Balancing oxidative protein folding: the influences of reducing pathways on disulfide bond formation.Biochim Biophys Acta2014;1844:1383-90

[53] Sjöström AE,Uhlin BE.Membrane vesicle-mediated release of bacterial RNA.Sci Rep2015;5:15329 PMCID:PMC4612299

[54] Bitto NJ,Pidot S.Bacterial membrane vesicles transport their DNA cargo into host cells.Sci Rep2017;7:7072 PMCID:PMC5539193

[55] Pérez-Cruz C,López-Iglesias C.Outer-inner membrane vesicles naturally secreted by gram-negative pathogenic bacteria.PLoS One2015;10:e0116896 PMCID:PMC4291224

[56] Li J,Zhang S.Outer membrane vesicles containing signalling molecules and active hydrolytic enzymes released by a coral pathogen Vibrio shilonii AK1.Environ Microbiol2016;18:3850-66

[57] Sarvarian P,Gholipour E.Application of emerging plant-derived nanoparticles as a novel approach for nano-drug delivery systems.Immunol Invest2022;51:1039-59

[58] Han R,Han Y,Liu H.Engineered plant extracellular vesicles for autoimmune diseases therapy.Nano Res2024;17:2857-73

[59] Yang C,Merlin D.Advances in plant-derived edible nanoparticle-based lipid nano-drug delivery systems as therapeutic nanomedicines.J Mater Chem B2018;6:1312-21 PMCID:PMC6053076

[60] Perut F,Avnet S.Strawberry-derived exosome-like nanoparticles prevent oxidative stress in human mesenchymal stromal cells.Biomolecules2021;11:87 PMCID:PMC7828105

[61] Zhang M,Prasad M.Edible ginger-derived nanoparticles: a novel therapeutic approach for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer.Biomaterials2016;101:321-40 PMCID:PMC4921206

[62] Li D,Yue J.Advances in bioactivity of microRNAs of plant-derived exosome-like nanoparticles and milk-derived extracellular vesicles.J Agric Food Chem2022;70:6285-99

[63] Gardiner C,Sahoo S.Techniques used for the isolation and characterization of extracellular vesicles: results of a worldwide survey.J Extracell Vesicles2016;5:32945 PMCID:PMC5090131

[64] Wu Q,Zhang C.Capturing nascent extracellular vesicles by metabolic glycan labeling-assisted microfluidics.Nat Commun2023;14:6541 PMCID:PMC10582105

[65] Li P,Lee SH,Gao Z.Progress in exosome isolation techniques.Theranostics2017;7:789-804 PMCID:PMC5327650

[66] Li J,Vanhoutte PM,Xu A.Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in apoe^-/-mice.Circulation2016;133:2434-46

[67] Liu JH,Liu ZZ.Extracellular vesicles from child gut microbiota enter into bone to preserve bone mass and strength.Adv Sci2021;8:2004831 PMCID:PMC8097336

[68] Zhan W,Huang X.Pueraria lobata-derived exosome-like nanovesicles alleviate osteoporosis by enhacning autophagy.J Control Release2023;364:644-53

[69] Hwang JH,Kim HS.Yam-derived exosome-like nanovesicles stimulate osteoblast formation and prevent osteoporosis in mice.J Control Release2023;355:184-98

[70] Yang M,Luo Q,Chen F.An efficient method to isolate lemon derived extracellular vesicles for gastric cancer therapy.J Nanobiotechnology2020;18:100 PMCID:PMC7370524

[71] Chen L,Zhao R.Bacterial cytoplasmic membranes synergistically enhance the antitumor activity of autologous cancer vaccines.Sci Transl Med2021;13:eabc2816

[72] Liu H,Zhang T.Engineered bacterial extracellular vesicles for osteoporosis therapy.Chem Eng J2022;450:138309

[73] Xie J,Haesebrouck F,Vandenbroucke RE.The tremendous biomedical potential of bacterial extracellular vesicles.Trends Biotechnol2022;40:1173-94

[74] Zhou H,Wang J.Aloe-derived vesicles enable macrophage reprogramming to regulate the inflammatory immune environment.Front Bioeng Biotechnol2023;11:1339941 PMCID:PMC10764618

[75] Díaz-Garrido N,Baldomà L.Microbiota-derived extracellular vesicles in interkingdom communication in the gut.J Extracell Vesicles2021;10:e12161 PMCID:PMC8568775

[76] Gonda A,Senthil GN.Exosomal survivin facilitates vesicle internalization.Oncotarget2018;9:34919-34 PMCID:PMC6201849

[77] Yao Z,Li X.Exosomes exploit the virus entry machinery and pathway to transmit alpha interferon-induced antiviral activity.J Virol2018;92:e01578-18 PMCID:PMC6258946

[78] Heusermann W,Trojer D.Exosomes surf on filopodia to enter cells at endocytic hot spots, traffic within endosomes, and are targeted to the ER.J Cell Biol2016;213:173-84 PMCID:PMC5084269

[79] Sung BH,Guerrero J.A live cell reporter of exosome secretion and uptake reveals pathfinding behavior of migrating cells.Nat Commun2020;11:2092 PMCID:PMC7190671

[80] Arya SB,Parent CA.The ins-and-outs of exosome biogenesis, secretion, and internalization.Trends Cell Biol2024;34:90-108 PMCID:PMC10811273

[81] Fitzner D,van Rossum D.Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis.J Cell Sci2011;124:447-58

[82] Cerezo-Magaña M,van Kuppevelt TH,Belting M.Hypoxic induction of exosome uptake through proteoglycan-dependent endocytosis fuels the lipid droplet phenotype in glioma.Mol Cancer Res2021;19:528-40

[83] Christianson HC,van Kuppevelt TH,Belting M.Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity.Proc Natl Acad Sci U S A2013;110:17380-5 PMCID:PMC3808637

[84] Tang T,Huang Y.Materials design by synthetic biology.Nat Rev Mater2021;6:332-50

[85] Li Y,Cheng K.Bacterial outer membrane vesicles presenting programmed death 1 for improved cancer immunotherapy via immune activation and checkpoint inhibition.ACS Nano2020;14:16698-711

[86] Cheng K,Li Y.Bioengineered bacteria-derived outer membrane vesicles as a versatile antigen display platform for tumor vaccination via Plug-and-Display technology.Nat Commun2021;12:2041 PMCID:PMC8024398

[87] Alvarez-Erviti L,Yin H,Lakhal S.Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes.Nat Biotechnol2011;29:341-5

[88] Whitley JA.Engineering extracellular vesicles to deliver CRISPR ribonucleoprotein for gene editing.J Extracell Vesicles2023;12:e12343 PMCID:PMC10507228

[89] Kempen DH,Hefferan TE.Retention of in vitro and in vivo BMP-2 bioactivities in sustained delivery vehicles for bone tissue engineering.Biomaterials2008;29:3245-52 PMCID:PMC2577841

[90] Hay JJ,Petaroudi M.Bacteria-based materials for stem cell engineering.Adv Mater2018;30:e1804310

[91] Liu Y,Jia S.Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation.J Clin Invest2012;122:3101-13 PMCID:PMC3428080

[92] Lu Y,Wang J.Engineering bacteria‐activated multifunctionalized hydrogel for promoting diabetic wound healing.Adv Funct Mater2021;31:2105749

[93] Hu Y,Zhang Q.Exosome-guided bone targeted delivery of Antagomir-188 as an anabolic therapy for bone loss.Bioact Mater2021;6:2905-13 PMCID:PMC7917458

[94] Thomas SC,Kamble NS,Pauletti GM.Engineered bacteria enhance immunotherapy and targeted therapy through stromal remodeling of tumors.Adv Healthc Mater2022;11:e2101487 PMCID:PMC8770579

[95] Zhang Y,Sretenovic S.The emerging and uncultivated potential of CRISPR technology in plant science.Nat Plants2019;5:778-94

[96] Demirer GS,Jackson CT.Nanotechnology to advance CRISPR-Cas genetic engineering of plants.Nat Nanotechnol2021;16:243-50 PMCID:PMC10461802

[97] Lai CP,Ericsson M.Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter.ACS Nano2014;8:483-94 PMCID:PMC3934350

[98] Lv Q,Lu Y.Thermosensitive exosome-liposome hybrid nanoparticle-mediated chemoimmunotherapy for improved treatment of metastatic peritoneal cancer.Adv Sci2020;7:2000515 PMCID:PMC7509655

[99] Li Z,Wei M.In vitro and in vivo RNA inhibition by CD9-HuR functionalized exosomes encapsulated with miRNA or CRISPR/dCas9.Nano Lett2019;19:19-28

[100] Kim H,Mun D.Cardiac-specific delivery by cardiac tissue-targeting peptide-expressing exosomes.Biochem Biophys Res Commun2018;499:803-8

[101] Hung ME.Stabilization of exosome-targeting peptides via engineered glycosylation.J Biol Chem2015;290:8166-72 PMCID:PMC4375473

[102] Zhang C,Chang M.Exosome-delivered syndecan-1 rescues acute lung injury via a FAK/p190RhoGAP/RhoA/ROCK/NF-κB signaling axis and glycocalyx enhancement.Exp Cell Res2019;384:111596

[103] Liang G,Ali DJ.Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer.J Nanobiotechnology2020;18:10 PMCID:PMC6950820

[104] Liang Y,Li X.Chondrocyte-targeted microRNA delivery by engineered exosomes toward a cell-free osteoarthritis therapy.ACS Appl Mater Interfaces2020;12:36938-47

[105] Liang G,Zhu Y,Feng W.Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells.Int J Nanomedicine2018;13:585-99 PMCID:PMC5796471

[106] Liu HY,Zhong C.Rapid capture of cancer extracellular vesicles by lipid patch microarrays.Adv Mater2021;33:e2008493 PMCID:PMC11468818

[107] Yang L,Zhan Q.Blood TfR+ exosomes separated by a pH-responsive method deliver chemotherapeutics for tumor therapy.Theranostics2019;9:7680-96 PMCID:PMC6831460

[108] Tamura R,Tabata Y.Augmented liver targeting of exosomes by surface modification with cationized pullulan.Acta Biomater2017;57:274-84

[109] Nakase I.Combined treatment with a pH-sensitive fusogenic peptide and cationic lipids achieves enhanced cytosolic delivery of exosomes.Sci Rep2015;5:10112 PMCID:PMC4443764

[110] Cheng H,Zhao LP.Chimeric peptide engineered exosomes for dual-stage light guided plasma membrane and nucleus targeted photodynamic therapy.Biomaterials2019;211:14-24

[111] Gao X,Dong X.Anchor peptide captures, targets, and loads exosomes of diverse origins for diagnostics and therapy.Sci Transl Med2018;10:eaat0195

[112] Wu P,Ocansey DKW,Qian H.Extracellular vesicles: a bright star of nanomedicine.Biomaterials2021;269:120467

[113] Koo S,Kim TH.Ceria-vesicle nanohybrid therapeutic for modulation of innate and adaptive immunity in a collagen-induced arthritis model.Nat Nanotechnol2023;18:1502-14

[114] Fang RH,Gao W.Cell membrane coating nanotechnology.Adv Mater2018;30:e1706759 PMCID:PMC5984176

[115] Chen Q,Wu W.A hybrid eukaryotic-prokaryotic nanoplatform with photothermal modality for enhanced antitumor vaccination.Adv Mater2020;32:e1908185

[116] Salunkhe S,Basak M,Mittal A.Surface functionalization of exosomes for target-specific delivery and in vivo imaging & tracking: strategies and significance.J Control Release2020;326:599-614

[117] Piffoux M,Wilhelm C,Tareste D.Modification of extracellular vesicles by fusion with liposomes for the design of personalized biogenic drug delivery systems.ACS Nano2018;12:6830-42

[118] Lin Y,Gu W.Exosome-liposome hybrid nanoparticles deliver CRISPR/Cas9 system in MSCs.Adv Sci2018;5:1700611 PMCID:PMC5908366

[119] Saari H,Viitala T,Siljander P.Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of Paclitaxel in autologous prostate cancer cells.J Control Release2015;220:727-37

[120] Pascucci L,Bonomi A.Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery.J Control Release2014;192:262-70

[121] Yong T,Bie N.Tumor exosome-based nanoparticles are efficient drug carriers for chemotherapy.Nat Commun2019;10:3838 PMCID:PMC6707218

[122] Jung KO,Yu JH,Pratx G.Development and MPI tracking of novel hypoxia-targeted theranostic exosomes.Biomaterials2018;177:139-48 PMCID:PMC6019194

[123] Li YJ,Wang JM,Cai JX.Gemcitabine loaded autologous exosomes for effective and safe chemotherapy of pancreatic cancer.Acta Biomater2020;101:519-30

[124] Wei H,Wang S.A nanodrug consisting of doxorubicin and exosome derived from mesenchymal stem cells for osteosarcoma treatment in vitro.Int J Nanomedicine2019;14:8603-10 PMCID:PMC6830377

[125] Sun L,Huang D.Clodronate-loaded liposomal and fibroblast-derived exosomal hybrid system for enhanced drug delivery to pulmonary fibrosis.Biomaterials2021;271:120761

[126] Jia G,An Y.NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo.Biomaterials2018;178:302-16

[127] Lee J,Goh U.Cellular engineering with membrane fusogenic liposomes to produce functionalized extracellular vesicles.ACS Appl Mater Interfaces2016;8:6790-5

[128] Zhou HY,Wang C.A transformer-based representation-learning model with unified processing of multimodal input for clinical diagnostics.Nat Biomed Eng2023;7:743-55

[129] Zhang K,Shen J.Clinically applicable AI system for accurate diagnosis, quantitative measurements, and prognosis of COVID-19 pneumonia using computed tomography.Cell2020;181:1423-33.e11 PMCID:PMC7196900

[130] Monzel AS,Kaoma T.Machine learning-assisted neurotoxicity prediction in human midbrain organoids.Parkinsonism Relat Disord2020;75:105-9

[131] Bai L,Li G,Zhang H.AI-enabled organoids: construction, analysis, and application.Bioact Mater2024;31:525-48 PMCID:PMC10511344

[132] Guo H.Engineered exosomes for future gene-editing therapy.Biomater Transl2022;3:240-2 PMCID:PMC9947735

[133] García-Barberán V,Guamán HM.The times they are AI-changing: AI-powered advances in the application of extracellular vesicles to liquid biopsy in breast cancer.Extracell Vesicles Circ Nucl Acids2025;6:128-40 PMCID:PMC11977355

[134] Wang J,Wang S,Jing Y.Bone aging and extracellular vesicles.Sci Bull2024;69:3978-99

[135] Yang J,Tian X,Li Y.Progress in understanding oxidative stress, aging, and aging-related diseases.Antioxidants2024;13:394 PMCID:PMC11047596

[136] Fang F,Wang J.The role and applications of extracellular vesicles in osteoporosis.Bone Res2024;12:4 PMCID:PMC10806231

[137] Elashiry M,Elsayed R.Dendritic cell derived exosomes loaded with immunoregulatory cargo reprogram local immune responses and inhibit degenerative bone disease in vivo.J Extracell Vesicles2020;9:1795362 PMCID:PMC7480413

[138] Song H,Zhao Z.Reversal of osteoporotic activity by endothelial cell-secreted bone targeting and biocompatible exosomes.Nano Lett2019;19:3040-8

[139] Wei Y,Zhang J.Extracellular vesicles derived from the mid-to-late stage of osteoblast differentiation markedly enhance osteogenesis in vitro and in vivo.Biochem Biophys Res Commun2019;514:252-8

[140] Gatti M,Zavatti M.Amniotic fluid stem cell-derived extracellular vesicles counteract steroid-induced osteoporosis in vitro.Int J Mol Sci2020;22:38 PMCID:PMC7792960

[141] Sonoda S,Nishida K.Extracellular vesicles from deciduous pulp stem cells recover bone loss by regulating telomerase activity in an osteoporosis mouse model.Stem Cell Res Ther2020;11:296 PMCID:PMC7367365

[142] Nakao Y,Zhang Q.Exosomes from TNF-α-treated human gingiva-derived MSCs enhance M2 macrophage polarization and inhibit periodontal bone loss.Acta Biomater2021;122:306-24 PMCID:PMC7897289

[143] Chen CY,Tan YJ.Extracellular vesicles from human urine-derived stem cells prevent osteoporosis by transferring CTHRC1 and OPG.Bone Res2019;7:18 PMCID:PMC6594995

[144] Qi X,Yuan H.Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats.Int J Biol Sci2016;12:836-49 PMCID:PMC4910602

[145] Xiao F,Tao B.Exosomes derived from cyclic mechanical stretch-exposed bone marrow mesenchymal stem cells inhibit RANKL-induced osteoclastogenesis through the NF-κB signaling pathway.Ann Transl Med2021;9:798 PMCID:PMC8246225

[146] Zhang L,Su H.Exosomes from adipose derived mesenchymal stem cells alleviate diabetic osteoporosis in rats through suppressing NLRP3 inflammasome activation in osteoclasts.J Biosci Bioeng2021;131:671-8

[147] Hu Y,Ni CY.Human umbilical cord mesenchymal stromal cells-derived extracellular vesicles exert potent bone protective effects by CLEC11A-mediated regulation of bone metabolism.Theranostics2020;10:2293-308 PMCID:PMC7019162

[148] Wang T,Ou J.Proteus mirabilis vesicles induce mitochondrial apoptosis by regulating miR96-5p/abca1 to inhibit osteoclastogenesis and bone loss.Front Immunol2022;13:833040 PMCID:PMC8885728

[149] Jiang Y,Xue X,Xu K.Engineered extracellular vesicles for bone therapy.Nano Today2022;44:101487

[150] Ma S,Huang H.Skeletal muscle-derived extracellular vesicles transport glycolytic enzymes to mediate muscle-to-bone crosstalk.Cell Metab2023;35:2028-43.e7

[151] Scheideler M,Zaragosi LE.Comparative transcriptomics of human multipotent stem cells during adipogenesis and osteoblastogenesis.BMC Genomics2008;9:340 PMCID:PMC2492879

[152] Niedermair T,Li S.Influence of extracellular vesicles isolated from osteoblasts of patients with Cox-arthrosis and/or osteoporosis on metabolism and osteogenic differentiation of BMSCs.Front Bioeng Biotechnol2020;8:615520 PMCID:PMC7785908

[153] Li D,Guo B.Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation.Nat Commun2016;7:10872 PMCID:PMC4786676

[154] He J,Wang Z.Therapeutic anabolic and anticatabolic benefits of natural Chinese medicines for the treatment of osteoporosis.Front Pharmacol2019;10:1344 PMCID:PMC6886594

[155] Liu Z,Fang L,Wang X.Breakthrough of extracellular vesicles in pathogenesis, diagnosis and treatment of osteoarthritis.Bioact Mater2023;22:423-52 PMCID:PMC9588998

[156] Peng Q.The potential of protein-nanomaterial interaction for advanced drug delivery.J Control Release2016;225:121-32

[157] Yin B,Witherel CE.Harnessing tissue-derived extracellular vesicles for osteoarthritis theranostics.Theranostics2022;12:207-31 PMCID:PMC8690930

[158] Zhang X,Kraus VB.Extracellular vesicles as biological indicators and potential sources of autologous therapeutics in osteoarthritis.Int J Mol Sci2021;22:8351 PMCID:PMC8347326

[159] Zhao Y.Synovial fluid-derived exosomal lncRNA PCGEM1 as biomarker for the different stages of osteoarthritis.Int Orthop2018;42:2865-72

[160] Rosenthal AK,Ninomiya J.Proteomic analysis of articular cartilage vesicles from normal and osteoarthritic cartilage.Arthritis Rheum2011;63:401-11 PMCID:PMC3038242

[161] Kolhe R,Liu S.Gender-specific differential expression of exosomal miRNA in synovial fluid of patients with osteoarthritis.Sci Rep2017;7:2029 PMCID:PMC5435729

[162] Jin Y,Zhu H.Therapeutic effects of bone marrow mesenchymal stem cells-derived exosomes on osteoarthritis.J Cell Mol Med2021;25:9281-94 PMCID:PMC8500984

[163] Wang X,Cui Y,Chen C.Exosomes isolated from bone marrow mesenchymal stem cells exert a protective effect on osteoarthritis via lncRNA LYRM4-AS1-GRPR-miR-6515-5p.Front Cell Dev Biol2021;9:644380 PMCID:PMC8193855

[164] Zhang J,Luo C.Bone marrow mesenchymal stem cell-derived exosomes prevent osteoarthritis by regulating synovial macrophage polarization.Aging2020;12:25138-52 PMCID:PMC7803581

[165] Woo CH,Jung GY.Small extracellular vesicles from human adipose-derived stem cells attenuate cartilage degeneration.J Extracell Vesicles2020;9:1735249 PMCID:PMC7144299

[166] Cavallo C,Borzì RM.Small extracellular vesicles from adipose derived stromal cells significantly attenuate in vitro the NF-κB dependent inflammatory/catabolic environment of osteoarthritis.Sci Rep2021;11:1053 PMCID:PMC7806716

[167] Qiu M,Fu Q.MiR-129-5p shuttled by human synovial mesenchymal stem cell-derived exosomes relieves IL-1β induced osteoarthritis via targeting HMGB1.Life Sci2021;269:118987

[168] Lu L,Fan A.Synovial mesenchymal stem cell-derived extracellular vesicles containing microRN555A-26a-5p ameliorate cartilage damage of osteoarthritis.J Gene Med2021;23:e3379

[169] Luo P,Ji P,Xu J.Exosomes of stem cells from human exfoliated deciduous teeth as an anti-inflammatory agent in temporomandibular joint chondrocytes via miR-100-5p/mTOR.Stem Cell Res Ther2019;10:216 PMCID:PMC6664713

[170] Ragni E,Perucca Orfei C.Amniotic membrane-mesenchymal stromal cells secreted factors and extracellular vesicle-miRNAs: Anti-inflammatory and regenerative features for musculoskeletal tissues.Stem Cells Transl Med2021;10:1044-62 PMCID:PMC8235131

[171] Li K,Huang H.Anti-inflammatory and immunomodulatory effects of the extracellular vesicles derived from human umbilical cord mesenchymal stem cells on osteoarthritis via M2 macrophages.J Nanobiotechnology2022;20:38 PMCID:PMC8771624

[172] Li X,Cai Z,Li L.Exosomes from human umbilical cord mesenchymal stem cells inhibit ROS production and cell apoptosis in human articular chondrocytes via the miR-100-5p/NOX4 axis.Cell Biol Int2021;45:2096-106

[173] Wang Y,Liu Z.Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix.Stem Cell Res Ther2017;8:189 PMCID:PMC5556343

[174] Zhang S,Chuah SJ,Lim SK.MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis.Biomaterials2019;200:35-47

[175] Zavatti M,Casciaro F,Maraldi T.Comparison of the therapeutic effect of amniotic fluid stem cells and their exosomes on monoiodoacetate-induced animal model of osteoarthritis.Biofactors2020;46:106-17

[176] Otahal A,Kuten-Pella O.Effects of extracellular vesicles from blood-derived products on osteoarthritic chondrocytes within an inflammation model.Int J Mol Sci2021;22:7224 PMCID:PMC8267849

[177] Liu X,Ma C,Zhang Y.Exosomes derived from platelet-rich plasma present a novel potential in alleviating knee osteoarthritis by promoting proliferation and inhibiting apoptosis of chondrocyte via Wnt/β-catenin signaling pathway.J Orthop Surg Res2019;14:470 PMCID:PMC6936129

[178] Bai J,Zheng X.LncRNA MM2P-induced, exosome-mediated transfer of Sox9 from monocyte-derived cells modulates primary chondrocytes.Cell Death Dis2020;11:763 PMCID:PMC7494881

[179] Zheng L,Qiu P.Primary chondrocyte exosomes mediate osteoarthritis progression by regulating mitochondrion and immune reactivity.Nanomedicine2019;14:3193-212

[180] Xu T,Bai J.Tenocyte-derived exosomes induce the tenogenic differentiation of mesenchymal stem cells through TGF-β.Cytotechnology2019;71:57-65 PMCID:PMC6368508

[181] Jo SH,Park SH.Novel marine organism-derived extracellular vesicles for control of anti-inflammation.Tissue Eng Regen Med2021;18:71-9 PMCID:PMC7862483

[182] Lei J,Li W.Exosomes from antler stem cells alleviate mesenchymal stem cell senescence and osteoarthritis.Protein Cell2022;13:220-6 PMCID:PMC8901817

[183] Arntz OJ,Oliveira MC.Oral administration of bovine milk derived extracellular vesicles attenuates arthritis in two mouse models.Mol Nutr Food Res2015;59:1701-12

[184] Song Y,Xu H.Mesenchymal stem cells in knee osteoarthritis treatment: a systematic review and meta-analysis.J Orthop Translat2020;24:121-30 PMCID:PMC7452318

[185] Ankrum JA,Karp JM.Mesenchymal stem cells: immune evasive, not immune privileged.Nat Biotechnol2014;32:252-60 PMCID:PMC4320647

[186] Damjanov I.Teratomas produced from human pluripotent stem cells xenografted into immunodeficient mice - a histopathology atlas.Int J Dev Biol2016;60:337-419 PMCID:PMC5338735

[187] He L,Xing J.Bone marrow mesenchymal stem cell-derived exosomes protect cartilage damage and relieve knee osteoarthritis pain in a rat model of osteoarthritis.Stem Cell Res Ther2020;11:276 PMCID:PMC7350730

[188] Tassara M,Barzizza L.Autologous conditioned serum (ACS) for intra-articular treatment in osteoarthritis: retrospective report of 28 cases.Transfus Apher Sci2018;57:573-7

[189] Cai Z,Wang H,Liu X.Extracellular vesicle-contained thrombospondin 1 retards age-related degenerative tendinopathy by rejuvenating tendon stem/progenitor cell senescence.Small2024;20:e2400598

[190] Liu H,Wang M,Su J.Intestinal organoids and organoids extracellular vesicles for inflammatory bowel disease treatment.Chem Eng J2023;465:142842

[191] Gao H,Huang X.Extracellular vesicles from organoid-derived human retinal progenitor cells prevent lipid overload-induced retinal pigment epithelium injury by regulating fatty acid metabolism.J Extracell Vesicles2024;13:e12401 PMCID:PMC10752800

[192] Abe K,Morioka M.Engraftment of allogeneic iPS cell-derived cartilage organoid in a primate model of articular cartilage defect.Nat Commun2023;14:804 PMCID:PMC9941131

[193] Shen C,Li G.Boosting cartilage repair with silk fibroin-DNA hydrogel-based cartilage organoid precursor.Bioact Mater2024;35:429-44 PMCID:PMC10881360

[194] Xu X,Li X.Exosome-mediated delivery of kartogenin for chondrogenesis of synovial fluid-derived mesenchymal stem cells and cartilage regeneration.Biomaterials2021;269:120539

[195] Li S,Lukas C.Curcumin-primed human BMSC-derived extracellular vesicles reverse IL-1β-induced catabolic responses of OA chondrocytes by upregulating miR-126-3p.Stem Cell Res Ther2021;12:252 PMCID:PMC8082633

[196] Xu C,Ying H,Zhang J.Curcumin primed ADMSCs derived small extracellular vesicle exert enhanced protective effects on osteoarthritis by inhibiting oxidative stress and chondrocyte apoptosis.J Nanobiotechnology2022;20:123 PMCID:PMC8905866

[197] Rong Y,Jiang D.Hypoxic pretreatment of small extracellular vesicles mediates cartilage repair in osteoarthritis by delivering miR-216a-5p.Acta Biomater2021;122:325-42

[198] Wan S,Li J.Extracellular vesicles from hypoxic pretreated urine-derived stem cells enhance the proliferation and migration of chondrocytes by delivering miR-26a-5p.Cartilage2022;13:19476035221077401 PMCID:PMC9137301

[199] Zhou Y,Li Y.Exosomes derived from miR-126-3p-overexpressing synovial fibroblasts suppress chondrocyte inflammation and cartilage degradation in a rat model of osteoarthritis.Cell Death Discov2021;7:37 PMCID:PMC7904758

[200] Dong J,Fang X.Exosome-encapsulated microRNA-127-3p released from bone marrow-derived mesenchymal stem cells alleviates osteoarthritis through regulating CDH11-mediated Wnt/β-catenin pathway.J Pain Res2021;14:297-310 PMCID:PMC7871222

[201] Tao Y,Wang Z.Human bone mesenchymal stem cells-derived exosomal miRNA-361-5p alleviates osteoarthritis by downregulating DDX20 and inactivating the NF-κB signaling pathway.Bioorg Chem2021;113:104978

[202] Li M,Sun M,Hu M.Extracellular vesicles as bioactive nanotherapeutics: an emerging paradigm for regenerative medicine.Theranostics2022;12:4879-903 PMCID:PMC9274746

[203] Liu H,Zhang H.Synthetic biology-based bacterial extracellular vesicles displaying BMP-2 and CXCR4 to ameliorate osteoporosis.J Extracell Vesicles2024;13:e12429 PMCID:PMC10995478

[204] Divakaruni AS,Minarrieta L.Etomoxir inhibits macrophage polarization by disrupting CoA homeostasis.Cell Metab2018;28:490-503.e7 PMCID:PMC6125190

[205] Rahman SO,Mobasheri A.The potential role of probiotics in the management of osteoarthritis pain: current status and future prospects.Curr Rheumatol Rep2023;25:307-26 PMCID:PMC10754743

[206] Wen M,Ou Z.Bacterial extracellular vesicles: a position paper by the microbial vesicles task force of the Chinese society for extracellular vesicles.Interdiscip Med2023;1:e20230017

[207] Zhuang X,Mu J.Ginger-derived nanoparticles protect against alcohol-induced liver damage.J Extracell Vesicles2015;4:28713 PMCID:PMC4662062

[208] Wang B,Deng ZB.Targeted drug delivery to intestinal macrophages by bioactive nanovesicles released from grapefruit.Mol Ther2014;22:522-34 PMCID:PMC3944329

[209] You JY,Rhee WJ.Isolation of cabbage exosome-like nanovesicles and investigation of their biological activities in human cells.Bioact Mater2021;6:4321-32 PMCID:PMC8105599

[210] De Robertis M,D’Oria V.Blueberry-derived exosome-like nanoparticles counter the response to TNF-α-induced change on gene expression in EA.hy926 cells.Biomolecules2020;10:742 PMCID:PMC7277966

[211] Zhang H,Li C.Exosome-induced regulation in inflammatory bowel disease.Front Immunol2019;10:1464 PMCID:PMC6611439

[212] Aquilano K,Gismondi A.Adipocyte metabolism is improved by TNF receptor-targeting small RNAs identified from dried nuts.Commun Biol2019;2:317 PMCID:PMC6704100

[213] Song H,Ngo VL,Garg P.Internalization of garlic-derived nanovesicles on liver cells is triggered by interaction with CD98.ACS Omega2020;5:23118-28 PMCID:PMC7495725

[214] Chen X,Yu J.Exosome-like nanoparticles from ginger rhizomes inhibited NLRP3 inflammasome activation.Mol Pharm2019;16:2690-9

[215] Matías J,Cenoz S.Oral immunogenicity in mice and sows of enterotoxigenic Escherichia Coli outer-membrane vesicles incorporated into zein-based nanoparticles.Vaccines2019;8:11 PMCID:PMC7157560

[216] Liu H,Wang S,Jing Y.Bacterial extracellular vesicles as bioactive nanocarriers for drug delivery: advances and perspectives.Bioact Mater2022;14:169-81 PMCID:PMC8892084

[217] Shah R,Freedman JE.Circulating extracellular vesicles in human disease.N Engl J Med2018;379:958-66

[218] Teng Y,Zhang X.Plant-derived exosomal microRNAs inhibit lung inflammation induced by exosomes SARS-CoV-2 Nsp12.Mol Ther2021;29:2424-40 PMCID:PMC8110335

[219] Ji N,Wang M,Liu H.Engineered bacterial extracellular vesicles for central nervous system diseases.J Control Release2023;364:46-60

[220] Andreu Z,Sanguino-Pascual A.Comparative analysis of EV isolation procedures for miRNAs detection in serum samples.J Extracell Vesicles2016;5:31655 PMCID:PMC4916259

[221] Yang L.Adipose tissue-derived extracellular vesicle microRNAs: diagnostic biomarkers for the pathophysiology associated with obesity.Precis Chem2025;3:480-91 PMCID:PMC12458052

[222] Ho MY,Xing B.Bacteria extracellular vesicle as nanopharmaceuticals for versatile biomedical potential.Nano Converg2024;11:28 PMCID:PMC11239649

[223] Liu H.Organoid extracellular vesicle-based therapeutic strategies for bone therapy.Biomater Transl2023;4:199-212 PMCID:PMC10817793

[224] Kumar MA,Sadida HQ.Extracellular vesicles as tools and targets in therapy for diseases.Signal Transduct Target Ther2024;9:27 PMCID:PMC10838959

[225] Kuo TR.Bone biomarker for the clinical assessment of osteoporosis: recent developments and future perspectives.Biomark Res2017;5:18 PMCID:PMC5436437

[226] Shi H,Xu C.MicroRNAs in serum exosomes as circulating biomarkers for postmenopausal osteoporosis.Front Endocrinol2022;13:819056 PMCID:PMC8960856

[227] McCarty NS.Synthetic biology tools to engineer microbial communities for biotechnology.Trends Biotechnol2019;37:181-97 PMCID:PMC6340809

[228] Yue Y,Li Y.Antigen-bearing outer membrane vesicles as tumour vaccines produced in situ by ingested genetically engineered bacteria.Nat Biomed Eng2022;6:898-909

[229] Ou Z,Huang X.Single-particle analysis of circulating bacterial extracellular vesicles reveals their biogenesis, changes in blood and links to intestinal barrier.J Extracell Vesicles2023;12:e12395 PMCID:PMC10696524

[230] Chen X,Xie J.Immunomodulatory effects of probiotic-derived extracellular vesicles: opportunities and challenges.J Agric Food Chem2024;72:19259-73

[231] Yang Z,Ding L.Nanoengineering multifunctional extracellular vesicles availably mitigate bone loss in osteoporosis through binding to RANKL and rebalancing the Treg/Th17 cells.Chem Eng J2023;467:143391

[232] Kim SQ.Emergence of edible plant-derived nanovesicles as functional food components and nanocarriers for therapeutics delivery: potentials in human health and disease.Cells2022;11:2232 PMCID:PMC9319657

[233] Trentesaux C,Klein OD.Harnessing synthetic biology to engineer organoids and tissues.Cell Stem Cell2023;30:10-9 PMCID:PMC11684341

[234] Liang W,Ravindran R.Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired.Nat Commun2023;14:5031 PMCID:PMC10439183

[235] Ma J,Yue D,Gao F.Extracellular vesicles from BMSCs prevent glucocorticoid-induced BMECs injury by regulating autophagy via the PI3K/Akt/mTOR pathway.Cells2022;11:2104 PMCID:PMC9265732

[236] Akbal A,Lovotti M,McManus RM.How location and cellular signaling combine to activate the NLRP3 inflammasome.Cell Mol Immunol2022;19:1201-14 PMCID:PMC9622870