Advanced small extracellular vesicles delivery systems for in situ tissue engineering

Abstract

In situ tissue engineering, which activates the body’s innate regenerative capacity, has demonstrated superior clinical translation potential than traditional ex situ approaches. Small extracellular vesicles (sEVs), as natural nanovesicles, can excellently mimic the paracrine functions of cells and are thus emerging as promising cell-free alternatives for in situ tissue engineering. Despite advantages such as low immunogenicity, multi-target regulatory capabilities, and cross biological barriers availability, the therapeutic sustainability of sEVs is limited by their rapid clearance in vivo, underscoring the need for effective delivery systems. This review systematically summarizes the sources and bioactivities of sEVs, delineates the design principles and technological advances in sEVs delivery systems, and highlights their application in tissue engineering, while also outlining future trajectories for the development of intelligent delivery platforms.

Keywords

In situ tissue engineering / sEVs / controlled delivery / hydrogels / surface modification

References

[1] Berthiaume F,Yarmush ML.Tissue engineering and regenerative medicine: history, progress, and challenges.Annu Rev Chem Biomol Eng.2011;2:403-30

[2] Gaharwar AK,Khademhosseini A.Engineered biomaterials for in situ tissue regeneration.Nat Rev Mater.2020;5:686-705

[3] Yuan Z,Gao C,Huang J.Controlled magnesium ion delivery system for in situ bone tissue engineering.J Control Release.2022;350:360-76

[4] Wan AC.Nanomaterials for in situ cell delivery and tissue regeneration.Adv Drug Delivery Rev.2010;62:731-40

[5] Safina I.Biomaterials for recruiting and activating endogenous stem cells in situ tissue regeneration.Acta Biomater.2022;143:26-38 PMCID:PMC9035107

[6] Welsh JA, Goberdhan DCI, O’Driscoll L, et al.; MISEV Consortium. Minimal information for studies of extracellular vesicles (MISEV2023): from basic to advanced approaches. J Extracell Vesicles. 2024;13:e12404. PMCID:PMC10850029

[7] Cai Q,Wang S.Message in a bubble: shuttling small RNAs and proteins between cells and interacting organisms using extracellular vesicles.Annu Rev Plant Biol.2021;72:497-524 PMCID:PMC8369896

[8] Kim HY,Um W.Functional extracellular vesicles for regenerative medicine.Small.2022;18:e2106569

[9] Ma Y,Williams GR.Extracellular vesicle-embedded materials.J Control Release.2023;361:280-96

[10] Kamerkar S,Sugimoto H.Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer.Nature.2017;546:498-503 PMCID:PMC5538883

[11] Alvarez-Erviti L,Yin H,Lakhal S.Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes.Nat Biotechnol.2011;29:341-5

[12] Henriques-Antunes H,Zonari A.The kinetics of small extracellular vesicle delivery impacts skin tissue regeneration.ACS Nano.2019;13:8694-707

[13] Yang L,Rathnam C.Harnessing the therapeutic potential of extracellular vesicles for biomedical applications using multifunctional magnetic nanomaterials.Small.2022;18:e2104783 PMCID:PMC9344859

[14] Xiang J,Tseng S.Multifunctional MOF microneedle patch with adsorbed exosomes for enhanced diabetic wound healing.Mater Today Bio.2025;33:102076 PMCID:PMC12284567

[15] Tao Y,Jing F.Adipose-derived stem-cell-derived exosomes encapsulated patch for modulating inflammation and promoting tissue regeneration.ACS Nano.2025;19:21271-89

[16] Talebpour Amiri F, Omraninava M, Shahzamani S, Khodashenas A, Daryakar A, Nasiry D. Bioactive and degradable collagen-based three-dimensional scaffold encapsulated with adipose mesenchymal stem cells-derived exosomes improved diabetic wound healing.Regen Ther.2025;28:606-18 PMCID:PMC11891736

[17] Deng S,Cui X,Wang Q.Optimization of exosome-based cell-free strategies to enhance endogenous cell functions in tissue regeneration.Acta Biomater.2023;171:68-84

[18] Wang Y,Chen X.BMSC exosome-enriched acellular fish scale scaffolds promote bone regeneration.J Nanobiotechnol.2022;20:444 PMCID:PMC9555002

[19] Hu S,Lutz H.Dermal exosomes containing miR-218-5p promote hair regeneration by regulating β-catenin signaling.Sci Adv.2020;6:eaba1685 PMCID:PMC7439409

[20] Zhang Y,Zhu J.Exosome-loaded hyaluronic acid hydrogel composite with oxygen-producing 3D printed polylactic acid scaffolds for bone tissue repair and regeneration.Int J Biol Macromol.2024;274:132970

[21] Guo J,Hu Y.Exosome-based bone-targeting drug delivery alleviates impaired osteoblastic bone formation and bone loss in inflammatory bowel diseases.Cell Rep Med.2023;4:100881 PMCID:PMC9873828

[22] Song Y,Xu X.Adipose-derived mesenchymal stem cell-derived exosomes biopotentiated extracellular matrix hydrogels accelerate diabetic wound healing and skin regeneration.Adv Sci.2023;10:e2304023 PMCID:10602544

[23] Xiong J,Jia L.Bioinspired engineering ADSC nanovesicles thermosensitive hydrogel enhance autophagy of dermal papilla cells for androgenetic alopecia treatment.Bioact Mater.2024;36:112-25 PMCID:PMC10911949

[24] Hu N,Jiang X.Hypoxia-pretreated ADSC-derived exosome-embedded hydrogels promote angiogenesis and accelerate diabetic wound healing.Acta Biomater.2023;157:175-86

[25] Shen Z,Zhang Y.Chitosan hydrogel incorporated with dental pulp stem cell-derived exosomes alleviates periodontitis in mice via a macrophage-dependent mechanism.Bioact Mater.2020;5:1113-26 PMCID:PMC7371600

[26] Wang Y,Wang Y.Odontogenic exosomes simulating the developmental microenvironment promote complete regeneration of pulp-dentin complex in vivo.J Adv Res.2025;76:405-21 PMCID:PMC12793753

[27] Zhang Y,Li X.M2 macrophage exosome-derived lncRNA AK083884 protects mice from CVB3-induced viral myocarditis through regulating PKM2/HIF-1α axis mediated metabolic reprogramming of macrophages.Redox Biol.2024;69:103016 PMCID:PMC10792748

[28] Zheng X,Liu Y.Resveratrol-loaded macrophage exosomes alleviate multiple sclerosis through targeting microglia.J Control Release.2023;353:675-84

[29] Yuan M,Jiang T.GelMA/PEGDA microneedles patch loaded with HUVECs-derived exosomes and Tazarotene promote diabetic wound healing.J Nanobiotechnol.2022;20:147 PMCID:PMC8934449

[30] Faruqu FN,Zhou S,Al-Jamal KT.Defined serum-free three-dimensional culture of umbilical cord-derived mesenchymal stem cells yields exosomes that promote fibroblast proliferation and migration in vitro.FASEB J.2021;35:e21206 PMCID:7986687

[31] Tian T,He C.Targeted delivery of neural progenitor cell-derived extracellular vesicles for anti-inflammation after cerebral ischemia.Theranostics.2021;11:6507-21 PMCID:PMC8120222

[32] Cao Y,Liu Q.Dissolvable microneedle-based wound dressing transdermally and continuously delivers anti-inflammatory and pro-angiogenic exosomes for diabetic wound treatment.Bioact Mater.2024;42:32-51 PMCID:PMC11399477

[33] Wu L,Liu X.Milk-derived exosomes exhibit versatile effects for improved oral drug delivery.Acta Pharm Sin B.2022;12:2029-42 PMCID:PMC9279706

[34] Cao M,Han X.Ginseng-derived nanoparticles alter macrophage polarization to inhibit melanoma growth.J Immunother Cancer.2019;7:326 PMCID:PMC6882204

[35] Zhuang X,Mu J.Ginger-derived nanoparticles protect against alcohol-induced liver damage.J Extracell Vesicles.2015;4:28713 PMCID:4662062

[36] Zhu MZ,Liang YJ.Edible exosome-like nanoparticles from portulaca oleracea L mitigate DSS-induced colitis via facilitating double-positive CD4⁺CD8⁺T cells expansion.J Nanobiotechnol.2023;21:309 PMCID:10469825

[37] Jiang D,Liu H,Xia X.Plant exosome-like nanovesicles derived from sesame leaves as carriers for luteolin delivery: Molecular docking, stability and bioactivity.Food Chem.2024;438:137963

[38] Vizoso FJ,Cid S,Perez-Fernandez R.Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine.Int J Mol Sci.2017;18:1852 PMCID:PMC5618501

[39] Li Z,Tong K.BMSC-derived exosomes promote tendon-bone healing after anterior cruciate ligament reconstruction by regulating M1/M2 macrophage polarization in rats.Stem Cell Res Ther.2022;13:295 PMCID:PMC9284827

[40] Fan L,Chen X.Exosomes-loaded electroconductive hydrogel synergistically promotes tissue repair after spinal cord injury via immunoregulation and enhancement of myelinated axon growth.Adv Sci.2022;9:e2105586 PMCID:9069372

[41] Qin Y,Yang P.An update on adipose-derived stem cells for regenerative medicine: where challenge meets opportunity.Adv Sci.2023;10:e2207334 PMCID:10369252

[42] Xing H,Mao Q.Injectable exosome-functionalized extracellular matrix hydrogel for metabolism balance and pyroptosis regulation in intervertebral disc degeneration.J Nanobiotechnol.2021;19:264 PMCID:PMC8419940

[43] Zhu YG,Monsel A.Nebulized exosomes derived from allogenic adipose tissue mesenchymal stromal cells in patients with severe COVID-19: a pilot study.Stem Cell Res Ther.2022;13:220 PMCID:PMC9135389

[44] Ganesh V,Gomez-Contreras PC,Shin K.Exosome-based cell homing and angiogenic differentiation for dental pulp regeneration.Int J Mol Sci.2022;24:466 PMCID:PMC9820194

[45] Lee AE,Shi SH,Zhang QZ.DPSC-derived extracellular vesicles promote rat jawbone regeneration.J Dent Res.2023;102:313-21

[46] Liu C,Jiao G.Dental pulp stem cell-derived exosomes suppress M1 macrophage polarization through the ROS-MAPK-NFκB P65 signaling pathway after spinal cord injury.J Nanobiotechnol.2022;20:65 PMCID:PMC8811988

[47] Liang X,Tong X.Dental pulp mesenchymal stem cell-derived exosomes inhibit neuroinflammation and microglial pyroptosis in subarachnoid hemorrhage via the miRNA-197-3p/FOXO3 axis.J Nanobiotechnol.2024;22:426

[48] Hass R,Böhm S.Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC.Cell Commun Signal.2011;9:12 PMCID:PMC3117820

[49] Xie Y,Cheng Z.SHED-derived exosomes promote LPS-induced wound healing with less itching by stimulating macrophage autophagy.J Nanobiotechnol.2022;20:239 PMCID:PMC9124392

[50] Guo R,Zhang Y.SHED-derived exosomes attenuate trigeminal neuralgia after CCI of the infraorbital nerve in mice via the miR-24-3p/IL-1R1/p-p38 MAPK pathway.J Nanobiotechnol.2023;21:458 PMCID:PMC10685568

[51] Gao Y,Yuan X.Bioinspired porous microspheres for sustained hypoxic exosomes release and vascularized bone regeneration.Bioact Mater.2022;14:377-88 PMCID:PMC8964815

[52] Li D,Jin X.NK cell-derived exosomes carry miR-207 and alleviate depression-like symptoms in mice.J Neuroinflammation.2020;17:126 PMCID:PMC7178582

[53] Fang X,Zheng L,Zhu T.Reduced microRNA-744 expression in mast cell-derived exosomes triggers epithelial cell ferroptosis in acute respiratory distress syndrome.Redox Biol.2024;77:103387 PMCID:PMC11493202

[54] Zhang H,Xu M.M2 macrophage derived exosomal miR-20a-5p ameliorates trophoblast pyroptosis and placental injuries in obstetric antiphospholipid syndrome via the TXNIP/NLRP3 axis.Life Sci.2025;370:123561

[55] Luo H,Lin F.Macrophage exosomes mediate palmitic acid-induced metainflammation by transferring miR-3064-5p to target IκBα and activate NF-κB signaling.J Adv Res.2025;71:501-19 PMCID:PMC12126739

[56] Ye C,Zhu L,Hu Y.Macrophage-derived exosomal miR-2137 regulates pyroptosis in LPS-induced acute lung injury.Int Immunopharmacol.2024;143:113549

[57] Hsu AY,Pi X.Neutrophil-derived vesicles control complement activation to facilitate inflammation resolution.Cell.2025;188:1623-41.e26 PMCID:PMC11934499

[58] Liu Y,Wu H,Sun Y.Paeonol attenuated inflammatory response of endothelial cells via stimulating monocytes-derived exosomal microRNA-223.Front Pharmacol.2018;9:1105 PMCID:PMC6256086

[59] Wu T,Jian C.Regulatory T cell-derived exosome mediated macrophages polarization for osteogenic differentiation in fracture repair.J Control Release.2024;369:266-82

[60] Ribeiro-Rodrigues TM,Pereira-Carvalho R.Exosomes secreted by cardiomyocytes subjected to ischaemia promote cardiac angiogenesis.Cardiovasc Res.2017;113:1338-50

[61] Fu X,Chen L.Exosomes mediated fibrogenesis in dilated cardiomyopathy through a MicroRNA pathway.iScience.2023;26:105963 PMCID:PMC9932122

[62] Liu Y,Yu Y,Zhang C.Advances in the study of exosomes derived from mesenchymal stem cells and cardiac cells for the treatment of myocardial infarction.Cell Commun Signal.2023;21:202 PMCID:PMC10424417

[63] Qu M,Huang L.Dopamine-loaded blood exosomes targeted to brain for better treatment of Parkinson’s disease.J Control Release.2018;287:156-66

[64] Agrawal AK,Jeyabalan J.Milk-derived exosomes for oral delivery of paclitaxel.Nanomedicine.2017;13:1627-36

[65] Li Y,Wang L.Milk-derived exosomes as a promising vehicle for oral delivery of hydrophilic biomacromolecule drugs.Asian J Pharm Sci.2023;18:100797 PMCID:PMC10073618

[66] Zhao B,Jiang X.Exosome-like nanoparticles derived from fruits, vegetables, and herbs: innovative strategies of therapeutic and drug delivery.Theranostics.2024;14:4598-621 PMCID:PMC11373634

[67] Ye C,Bian SJ.Momordica charantia L.-derived exosome-like nanovesicles stabilize p62 expression to ameliorate doxorubicin cardiotoxicity.J Nanobiotechnol.2024;22:464 PMCID:PMC11297753

[68] 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.Biomaterials.2016;101:321-40 PMCID:PMC4921206

[69] Tembo KM,Bolideei M.Exploring the bioactivity of microRNAs originated from plant-derived exosome-like nanoparticles (PELNs): current perspectives.J Nanobiotechnol.2025;23:563 PMCID:PMC12344895

[70] Zhan W,Huang X.Pueraria lobata-derived exosome-like nanovesicles alleviate osteoporosis by enhacning autophagy.J Control Release.2023;364:644-53

[71] Gao XQ,Chen GJ.Ginsenoside Rb1 regulates the expressions of brain-derived neurotrophic factor and caspase-3 and induces neurogenesis in rats with experimental cerebral ischemia.J Ethnopharmacol.2010;132:393-9

[72] Wang Q,Mu J.Delivery of therapeutic agents by nanoparticles made of grapefruit-derived lipids.Nat Commun.2013;4:1867 PMCID:PMC4396627

[73] Gao C,Chen Z.Turmeric-derived nanovesicles as novel nanobiologics for targeted therapy of ulcerative colitis.Theranostics.2022;12:5596-614 PMCID:PMC9330521

[74] Li S,Wang A.Panax notoginseng: derived exosome-like nanoparticles attenuate ischemia reperfusion injury via altering microglia polarization.J Nanobiotechnol.2023;21:416 PMCID:PMC10636993

[75] Liu Y,Yu S.Exosomes derived from stem cells from apical papilla promote craniofacial soft tissue regeneration by enhancing Cdc42-mediated vascularization.Stem Cell Res Ther.2021;12:76 PMCID:PMC7821694

[76] Ju S,Dokland T.Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis.Mol Ther.2013;21:1345-57 PMCID:PMC3702113

[77] Ding K,Liu W.Engineering modification of human umbilical cord mesenchymal stem cell-derived small extracellular vesicles ameliorates polycystic ovary syndrome by enhancing the ovarian environment and regulating follicular development.Stem Cell Res Ther.2025;16:481 PMCID:PMC12403547

[78] Peng W,Cui W.Engineered small extracellular vesicles for targeted delivery of perlecan to stabilise the blood-spinal cord barrier after spinal cord injury.Clin Transl Med.2025;15:e70381 PMCID:PMC12179339

[79] Sun Y,Chen J.Surface-engineered umbilical cord mesenchymal stem cell-derived sevs for targeted therapy of osteoarthritis.ACS Biomater Sci Eng.2025;11:4725-36

[80] Ma L,Song Z.miR-423-5p-enriched small extracellular vesicles drive periodontal regeneration via Sfrp2+ cell expansion.Bioact Mater.2026;58:19-32 PMCID:PMC12703869

[81] Wei Q,Meng S.MiR-17-5p-engineered sEVs encapsulated in GelMA hydrogel facilitated diabetic wound healing by targeting PTEN and p21.Adv Sci.2024;11:e2307761 PMCID:PMC10987139

[82] Choi H,Yim HY,Yoo JK.Biodistribution of exosomes and engineering strategies for targeted delivery of therapeutic exosomes.Tissue Eng Regen Med.2021;18:499-511 PMCID:PMC8325750

[83] Wu J,Wang R.Exosomes secreted by stem cells from human exfoliated deciduous teeth promote alveolar bone defect repair through the regulation of angiogenesis and osteogenesis.ACS Biomater Sci Eng.2019;5:3561-71

[84] Li W,Zhang P.Tissue-engineered bone immobilized with human adipose stem cells-derived exosomes promotes bone regeneration.ACS Appl Mater Interfaces.2018;10:5240-54

[85] Su N,Wang F,Chen H.Mesenchymal stromal exosome-functionalized scaffolds induce innate and adaptive immunomodulatory responses toward tissue repair.Sci Adv.2021;7:eabf7207 PMCID:PMC8115917

[86] Yun JH,Yeou SH.Electrostatic attachment of exosome onto a 3D-fabricated calcium silicate/polycaprolactone for enhanced bone regeneration.Mater Today Bio.2024;29:101283 PMCID:PMC11480244

[87] Lee CS,Fan J,Aghaloo T.Smoothened agonist sterosome immobilized hybrid scaffold for bone regeneration.Sci Adv.2020;6:eaaz7822 PMCID:PMC7176430

[88] Fan L,Xiao C.Exosome-functionalized polyetheretherketone-based implant with immunomodulatory property for enhancing osseointegration.Bioact Mater.2021;6:2754-66 PMCID:PMC7897935

[89] Wei Y,Zhao R.MSC-derived sEVs enhance patency and inhibit calcification of synthetic vascular grafts by immunomodulation in a rat model of hyperlipidemia.Biomaterials.2019;204:13-24

[90] Pizzicannella J,Gugliandolo A.3D printing PLA/gingival stem cells/ EVs upregulate miR-2861 and -210 during osteoangiogenesis commitment.Int J Mol Sci.2019;20:3256 PMCID:PMC6651609

[91] Ying C,Wang Z.BMSC-exosomes carry mutant HIF-1α for improving angiogenesis and osteogenesis in critical-sized calvarial defects.Front Bioeng Biotechnol.2020;8:565561 PMCID:PMC7710518

[92] Zhang J,Li H.Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway.Stem Cell Res Ther.2016;7:136 PMCID:PMC5028974

[93] Li X,Hou L.Exosomes derived from maxillary BMSCs enhanced the osteogenesis in iliac BMSCs.Oral Dis.2020;26:131-44

[94] Kong W,Zhang C.Exosomes endow photocurable 3D printing 45S5 ceramic scaffolds to enhance angiogenesis-osteogenesis coupling for accelerated bone regeneration.Compos Part B Eng.2024;280:111455

[95] Zhai M,Yang M.Human mesenchymal stem cell derived exosomes enhance cell-free bone regeneration by altering their miRNAs profiles.Adv Sci.2020;7:2001334 PMCID:PMC7539212

[96] Wu Z,Su Z,Nie L.Schwann cell-derived exosomes promote bone regeneration and repair by enhancing the biological activity of porous Ti6Al4V scaffolds.Biochem Biophys Res Commun.2020;531:559-65

[97] Lu J,Zou D,Yang S.Graphene-modified titanium surface enhances local growth factor adsorption and promotes osteogenic differentiation of bone marrow stromal cells.Front Bioeng Biotechnol.2020;8:621788 PMCID:PMC7835422

[98] Wu Y,Tian S.Formation mechanism, degradation behavior, and cytocompatibility of a double-layered structural MAO/rGO-CaP coating on AZ31 Mg.Colloids Surf B Biointerfaces.2020;190:110901

[99] Sun X,Tong S.Study on exosomes promoting the osteogenic differentiation of ADSCs in graphene porous titanium alloy scaffolds.Front Bioeng Biotechnol.2022;10:905511 PMCID:PMC9207277

[100] Gandolfi MG,Zamparini F.Mineral-doped poly(L-lactide) acid scaffolds enriched with exosomes improve osteogenic commitment of human adipose-derived mesenchymal stem cells.Nanomaterials.2020;10:432 PMCID:PMC7153699

[101] Wei F,Crawford R,Xiao Y.Exosome-integrated titanium oxide nanotubes for targeted bone regeneration.Acta Biomater.2019;86:480-92

[102] He Q,Ao Q.Positive charge of chitosan retards blood coagulation on chitosan films.J Biomater Appl.2013;27:1032-45

[103] Lu X,Li L.Exosome-loaded methacrylated silk fibroin hydrogel delays intervertebral disc degeneration by DKK2-mediated mitochondrial unfolded protein response.Chem Eng J.2025;511:162191

[104] Yu L,Huang Y.A temperature-sensitive chitosan hydrogels loaded with nano-zinc oxide and exosomes from human umbilical vein endothelial cells accelerates wound healing.Regen Ther.2025;30:63-74 PMCID:PMC12146491

[105] Li J.Designing hydrogels for controlled drug delivery.Nat Rev Mater.2016;1:16071 PMCID:PMC5898614

[106] Mardpour S,Sadeghi-Abandansari H.Hydrogel-mediated sustained systemic delivery of mesenchymal stem cell-derived extracellular vesicles improves hepatic regeneration in chronic liver failure.ACS Appl Mater Interfaces.2019;11:37421-33

[107] Peng H,Zhang X.3D-exosomes laden multifunctional hydrogel enhances diabetic wound healing via accelerated angiogenesis.Chem Eng J.2023;475:146238

[108] He Y,Liu F.SHED-derived exosome-mimetics promotes rotator cuff tendon-bone healing via macrophage immunomodulation through NF-κB suppression and autophagy activation.Mater Today Bio.2025;34:102146 PMCID:PMC12345377

[109] Hua J,Xia W.Preparation and properties of EDC/NHS mediated crosslinking poly (gamma-glutamic acid)/epsilon-polylysine hydrogels.Mater Sci Eng C Mater Biol Appl.2016;61:879-92

[110] Scomazzon L,Dubus M.An increase in Wharton’s jelly membrane osteocompatibility by a genipin-cross-link.Int J Biol Macromol.2024;255:127562

[111] Shu QH,Chu M.Fiber-reinforced gelatin/β-cyclodextrin hydrogels loaded with platelet-rich plasma-derived exosomes for diabetic wound healing.Biomater Adv.2023;154:213640

[112] Zhang L,Wei P.Small intestinal submucosa membrane modified by fusion peptide-mediated extracellular vesicles to promote tissue regeneration.Adv Healthc Mater.2021;10:e2101298

[113] Ma S,Wu J.Functional extracellular matrix hydrogel modified with MSC-derived small extracellular vesicles for chronic wound healing.Cell Prolif.2022;55:e13196 PMCID:PMC9055911

[114] Ma S,Hu H.Novel fusion peptides deliver exosomes to modify injectable thermo-sensitive hydrogels for bone regeneration.Mater Today Bio.2022;13:100195 PMCID:PMC8724941

[115] Claes L,Ignatius A.Fracture healing under healthy and inflammatory conditions.Nat Rev Rheumatol.2012;8:133-43

[116] Lu Z,Dunstan C,Zreiqat H.Priming adipose stem cells with tumor necrosis factor-alpha preconditioning potentiates their exosome efficacy for bone regeneration.Tissue Eng Part A.2017;23:1212-20

[117] Cui Y,Li H,Han J.Exosomes derived from mineralizing osteoblasts promote ST2 cell osteogenic differentiation by alteration of microRNA expression.FEBS Lett.2016;590:185-92

[118] Lou W,Qin Y,Cao Y.3D-printed advanced scaffold armed with exosomes derived from human skeletal stem cell identified by single-cell RNA sequencing enhances osteochondral regeneration.Bioact Mater.2025;51:231-56 PMCID:PMC12141848

[119] Zhang W,Rnjak-Kovacina J.Vascularization of hollow channel-modified porous silk scaffolds with endothelial cells for tissue regeneration.Biomaterials.2015;56:68-77

[120] Xie H,Zhang L.Extracellular vesicle-functionalized decalcified bone matrix scaffolds with enhanced pro-angiogenic and pro-bone regeneration activities.Sci Rep.2017;7:45622 PMCID:PMC5377422

[121] Wang Y,Guo Y.Exosomes from tendon stem cells promote injury tendon healing through balancing synthesis and degradation of the tendon extracellular matrix.J Cell Mol Med.2019;23:5475-85 PMCID:PMC6653097

[122] Benjamin M,Ralphs JR,Best TM.Where tendons and ligaments meet bone: attachment sites (‘entheses’) in relation to exercise and/or mechanical load.J Anat.2006;208:471-90 PMCID:PMC2100202

[123] Chen H,Xiao H.Effect of exercise intensity on the healing of the bone-tendon interface: a mouse rotator cuff injury model study.Am J Sports Med.2021;49:2064-73

[124] Wang J,Wang X.Magnesium-pretreated periosteum for promoting bone-tendon healing after anterior cruciate ligament reconstruction.Biomaterials.2021;268:120576

[125] Xu J,Han K.Infrapatellar fat pad mesenchymal stromal cell-derived exosomes accelerate tendon-bone healing and intra-articular graft remodeling after anterior cruciate ligament reconstruction.Am J Sports Med.2022;50:662-73

[126] Fu G,Pan Z,Yin F.Adipose-derived stem cell exosomes facilitate rotator cuff repair by mediating tendon-derived stem cells.Regen Med.2021;16:359-72

[127] Huang Y,Wang L.Bone marrow mesenchymal stem cell-derived exosomes promote rotator cuff tendon-bone healing by promoting angiogenesis and regulating M1 macrophages in rats.Stem Cell Res Ther.2020;11:496 PMCID:PMC7687785

[128] Mascharak S,Januszyk M.Multi-omic analysis reveals divergent molecular events in scarring and regenerative wound healing.Cell Stem Cell.2022;29:315-27.e6 PMCID:PMC8988390

[129] Falanga V,Soulika AM.Chronic wounds.Nat Rev Dis Primers.2022;8:50 PMCID:PMC10352385

[130] Zhou Y,Zhang XL.Combined topical and systemic administration with human adipose-derived mesenchymal stem cells (hADSC) and hADSC-derived exosomes markedly promoted cutaneous wound healing and regeneration.Stem Cell Res Ther.2021;12:257 PMCID:PMC8088044

[131] Tian C,Li C.ADSC exosomes improve high glucose induced fibroblast oxidative stress injury and accelerate DFU wound healing via regulating Keap1/Nrf2 axis.Cell Signal.2025;134:111936

[132] Meng D,Wei X.hUC-MSCs exosomes-loaded hydrogels for systemic lupus erythematosus wound treatment.Chem Eng J.2025;521:166491

[133] Han M,Lu X.Three-dimensional-cultured MSC-derived exosome-hydrogel hybrid microneedle array patch for spinal cord repair.Nano Lett.2022;22:6391-401

[134] Luo Z,Xu Y.Exosomal OTULIN from M2 macrophages promotes the recovery of spinal cord injuries via stimulating Wnt/β-catenin pathway-mediated vascular regeneration.Acta Biomater.2021;136:519-32

[135] Serpa RO,Larson C.Pathophysiology of pediatric traumatic brain injury.Front Neurol.2021;12:696510 PMCID:PMC8319243

[136] Najem D,Ribecco-Lutkiewicz M.Traumatic brain injury: classification, models, and markers.Biochem Cell Biol.2018;96:391-406

[137] Li Y,Sun M.Engineering antioxidant poly (citrate-gallic acid)-exosome hybrid hydrogel with microglia immunoregulation for traumatic brain injury-post neuro-restoration.Compos Part B Eng.2022;242:110034

[138] Liu X,Zhang Y.Hyaluronan-based hydrogel integrating exosomes for traumatic brain injury repair by promoting angiogenesis and neurogenesis.Carbohydr Polym.2023;306:120578

[139] Kwak G,Kim H.Sustained exosome-guided macrophage polarization using hydrolytically degradable PEG hydrogels for cutaneous wound healing: identification of key proteins and MiRNAs, and sustained release formulation.Small.2022;18:e2200060

[140] Zhang Y,Chen J.Exosomes derived from platelet-rich plasma administration in site mediate cartilage protection in subtalar osteoarthritis.J Nanobiotechnol.2022;20:56 PMCID:PMC8801111

[141] Ma X,Xie X.Injectable and self-healable thermoresponsive hybrid hydrogel constructed via surface-modified graphene oxide loading exosomes for synergistic promotion of Schwann cells.ACS Appl. Nano Mater.2023;6:12425-38

[142] Wang C,Xu T.Engineering bioactive self-healing antibacterial exosomes hydrogel for promoting chronic diabetic wound healing and complete skin regeneration.Theranostics.2019;9:65-76 PMCID:PMC6332800