Targeting ferroptosis in photoaging: mechanisms and therapeutic potential of adipose-derived stem cell exosomes

Abstract

Skin photoaging is a form of premature cutaneous aging caused by chronic ultraviolet (UV) exposure, manifesting as wrinkling, laxity, and pigmentary disturbances. UV radiation generates reactive oxygen species and upregulates matrix metalloproteinases, leading to extracellular matrix degradation. Emerging evidence implicates ferroptosis - an iron-dependent form of regulated cell death characterized by lipid peroxidation - in ultraviolet B (UVB)-induced photodamage. Studies show that glutathione peroxidase 4 (GPX4)-dependent antioxidant defenses are compromised in UV-exposed skin cells, and ferroptosis inhibitors can partially attenuate UV-induced cellular damage. Exosomes derived from adipose-derived stem cells (ADSC-Exos) have emerged as a promising cell-free regenerative strategy for skin rejuvenation. These 30-150 nm extracellular vesicles offer advantages over whole-cell therapy, including low immunogenicity, reduced tumorigenic concerns compared with replicating cells, and easier standardization. Through paracrine signaling, ADSC-Exos deliver bioactive proteins and non-coding RNAs that promote collagen synthesis, angiogenesis, and anti-inflammatory effects. Circular RNAs (circRNAs) are highly enriched and stable in exosomes due to their covalently closed structure. Notably, hypoxic-preconditioned ADSC-Exos deliver circ-Ash1l into UVB-damaged skin cells, where it sequesters miR-700-5p and upregulates GPX4. This circ-Ash1l/miR-700-5p/GPX4 axis inhibits ferroptotic cell death, reduces oxidative damage, and attenuates UVB-induced photoaging phenotypes in vitro and in vivo. This review summarizes the mechanisms of UVB-mediated photoaging and ferroptosis, the therapeutic potential of adipose-derived stem cell-derived exosomes, the role of exosomal circRNAs, and engineering strategies to enhance exosome therapy. We also discuss clinical translation challenges, including manufacturing, quality control, and regulatory considerations.

Keywords

Photoaging / ferroptosis / adipose-derived stem cells / exosomes / GPX4 / circular RNA / skin rejuvenation

References

[1] Wong QYA.Defining skin aging and its risk factors: a systematic review and meta-analysis.Sci Rep.2021;11:22075 PMCID:PMC8586245

[2] Fisher GJ,Datta SC,Kang S.Pathophysiology of premature skin aging induced by ultraviolet light.N Engl J Med.1997;337:1419-28

[3] Krutmann J,Morita A.Environmentally-Induced (Extrinsic) Skin Aging: Exposomal Factors and Underlying Mechanisms.J Invest Dermatol.2021;141 Suppl:1096-103

[4] Zhang S.Fighting against Skin Aging: The Way from Bench to Bedside.Cell Transplant.2018;27:729-38 PMCID:PMC6047276

[5] Kim DJ,Chien AL.UVB-mediated DNA damage induces matrix metalloproteinases to promote photoaging in an AhR- and SP1-dependent manner.JCI Insight.2022;7 PMCID:PMC9090247

[6] Vats K,Mizes A.Keratinocyte death by ferroptosis initiates skin inflammation after UVB exposure.Redox Biol.2021;47:102143 PMCID:PMC8487085

[7] Zhang PC,Zong SQ.Variation of Ferroptosis-Related Markers in HaCaT Cell Photoaging Models Induced by UVB.Clin Cosmet Investig Dermatol.2023;16:3147-55

[8] Teng Y,Tao X,Fan Y.Ferrostatin 1 ameliorates UVB-induced damage of HaCaT cells by regulating ferroptosis.Exp Dermatol.2024;33:e15018

[9] Tang D,Kang R.Ferroptosis: molecular mechanisms and health implications.Cell Res.2021;31:107-25 PMCID:PMC8026611

[10] Xu P,Zhang Z.Extracellular vesicles from adipose-derived stem cells ameliorate ultraviolet B-induced skin photoaging by attenuating reactive oxygen species production and inflammation.Stem Cell Res Ther.2020;11:264 PMCID:PMC7329484

[11] Wang Y,Wang Y.Human adipose-derived stem cell exosomes reduce mitochondrial DNA common deletion through PINK1/Parkin-mediated mitophagy to improve skin photoaging.Stem Cell Res Ther.2025;16:365 PMCID:PMC12261646

[12] Liang C,Li J.Unveiling exosomes in combating skin aging: insights into resources, mechanisms and challenges.Stem Cell Res Ther.2025;16:474 PMCID:PMC12395928

[13] Park SY.Exosome-mediated advancements in plastic surgery: navigating therapeutic potential in skin rejuvenation and wound healing.Plast Reconstr Surg Glob Open.2024;12:e6021 PMCID:PMC11556992

[14] Zhang F,Qian H,Xu W.Exosomal circRNA: emerging insights into cancer progression and clinical application potential.J Hematol Oncol.2023;16:67 PMCID:PMC10294326

[15] Zha J,Liu X,Liu Y.Exosomes from hypoxia-pretreated adipose-derived stem cells attenuate ultraviolet light-induced skin injury via delivery of circ-Ash1l.Photodermatol Photoimmunol Photomed.2023;39:107-15

[16] Gromkowska-Kępka KJ,Markiewicz-Żukowska R.The impact of ultraviolet radiation on skin photoaging - review of in vitro studies.J Cosmet Dermatol.2021;20:3427-31 PMCID:PMC8597149

[17] Langton AK,Griffiths TW.Distinctive clinical and histological characteristics of atrophic and hypertrophic facial photoageing.J Eur Acad Dermatol Venereol.2021;35:762-8 PMCID:PMC7986784

[18] Boyd AS,Cameron GS,Gaskell SA.The effects of chronic sunscreen use on the histologic changes of dermatoheliosis.J Am Acad Dermatol.1995;33:941-6

[19] Widgerow AD.New approaches to skin photodamage histology-Differentiating ‘good’ versus ‘bad’ Elastin.J Cosmet Dermatol.2021;20:526-31 PMCID:PMC7898812

[20] Bernerd F,Castiel I.The damaging effects of long UVA (UVA1) rays: a major challenge to preserve skin health and integrity.Int J Mol Sci.2022;23:8243 PMCID:PMC9368482

[21] Cadet J,Ravanat JL.Oxidatively generated damage to cellular DNA by UVB and UVA radiation.Photochem Photobiol.2015;91:140-55

[22] Lawrence KP,Sarkany RPE,Herzog B.The UV/visible radiation boundary region (385-405 nm) damages skin cells and induces “dark” cyclobutane pyrimidine dimers in human skin in vivo.Sci Rep.2018;8:12722 PMCID:PMC6109054

[23] Fisher GJ,Talwar HS.Molecular basis of sun-induced premature skin ageing and retinoid antagonism.Nature.1996;379:335-9

[24] Koivukangas V,Autio-Harmainen H.UV irradiation induces the expression of gelatinases in human skin in vivo.Acta Derm Venereol.1994;74:279-82

[25] Quan T,Xia W,Voorhees JJ.Matrix-degrading metalloproteinases in photoaging.J Investig Dermatol Symp Proc.2009;14:20-4 PMCID:PMC2909639

[26] Fisher GJ,Wang Z.c-Jun-dependent inhibition of cutaneous procollagen transcription following ultraviolet irradiation is reversed by all-trans retinoic acid.J Clin Invest.2000;106:663-70 PMCID:PMC381286

[27] Green AC,McBride P.Factors associated with premature skin aging (photoaging) before the age of 55: a population-based study.Dermatology.2011;222:74-80

[28] Seité S,Moyal D.Alterations in human epidermal Langerhans cells by ultraviolet radiation: quantitative and morphological study.Br J Dermatol.2003;148:291-9

[29] Dumay O,Vian L.Ultraviolet AI exposure of human skin results in Langerhans cell depletion and reduction of epidermal antigen-presenting cell function: partial protection by a broad-spectrum sunscreen.Br J Dermatol.2001;144:1161-8

[30] Norval M.The consequences of UV-induced immunosuppression for human health.Photochem Photobiol.2011;87:965-77

[31] Ortonne JP.Pigmentary changes of the ageing skin.Br J Dermatol.1990;122:21-8

[32] Gilchrest BA,Szabo G.Effects of aging and chronic sun exposure on melanocytes in human skin.J Invest Dermatol.1979;73:141-3

[33] Le J,Wang Y.Molecular and therapeutic landscape of ferroptosis in skin diseases.Chin Med J.2024;137:1777-89 PMCID:PMC12077552

[34] Dixon SJ,Lamprecht MR.Ferroptosis: an iron-dependent form of nonapoptotic cell death.Cell.2012;149:1060-72 PMCID:PMC3367386

[35] Battaglia AM,Aversa I,Costanzo F.Ferroptosis and cancer: mitochondria meet the “iron maiden” cell death.Cells.2020;9:1505 PMCID:PMC7349567

[36] Lei P,Sun Y.Mechanisms of ferroptosis and relations with regulated cell death: a review.Front Physiol.2019;10:139 PMCID:PMC6399426

[37] Bersuker K,Li Z.The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis.Nature.2019;575:688-92 PMCID:PMC6883167

[38] Xiao T,Li M.ATG5-mediated keratinocyte ferroptosis promotes M1 polarization of macrophages to aggravate UVB-induced skin inflammation.J Photochem Photobiol B.2024;257:112948

[39] Pourzand C,Raczek NN.Shedding a new light on skin aging, iron- and redox-homeostasis and emerging natural antioxidants.Antioxidants.2022;11:471 PMCID:PMC8944509

[40] Kramer-Stickland K,Bair WB 3rd.Inhibitory effects of deferoxamine on UVB-induced AP-1 transactivation.Carcinogenesis.1999;20:2137-42

[41] Wang K,Zhou D.Unveiling ferroptosis: a new frontier in skin disease research.Front Immunol.2024;15:1485523 PMCID:PMC11486644

[42] Gurung S,Touramanidou L.The exosome journey: from biogenesis to uptake and intracellular signalling.Cell Commun Signal.2021;19:47 PMCID:PMC8063428

[43] Stoorvogel W,Geuze HJ.The biogenesis and functions of exosomes.Traffic.2002;3:321-30

[44] Joshi BS,Giepmans BNG.Endocytosis of extracellular vesicles and release of their cargo from endosomes.ACS Nano.2020;14:4444-55 PMCID:PMC7199215

[45] Abels ER.Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake.Cell Mol Neurobiol.2016;36:301-12 PMCID:PMC5546313

[46] Liu X,Lu L.Immunomodulatory potential of mesenchymal stem cell-derived extracellular vesicles: targeting immune cells.Front Immunol.2023;14:1094685 PMCID:PMC9968735

[47] Hajialiasgary Najafabadi A, Soheilifar MH, Masoudi-Khoram N. Exosomes in skin photoaging: biological functions and therapeutic opportunity.Cell Commun Signal.2024;22:32 PMCID:PMC10785444

[48] Zhang H,Wang L.Human adipose and umbilical cord mesenchymal stem cell-derived extracellular vesicles mitigate photoaging via TIMP1/Notch1.Signal Transduct Target Ther.2024;9:294 PMCID:PMC11522688

[49] Tan F,Wang Z,Shahzad K.Clinical applications of stem cell-derived exosomes.Signal Transduct Target Ther.2024;9:17 PMCID:PMC10784577

[50] Ahmadian S,Tamadon A,Rahbarghazi R.Different storage and freezing protocols for extracellular vesicles: a systematic review.Stem Cell Res Ther.2024;15:453 PMCID:PMC11600612

[51] El Baradie KBY,O’Brien Iii F.Freeze-dried extracellular vesicles from adipose-derived stem cells prevent hypoxia-induced muscle cell injury.Front Cell Dev Biol2020;8:181 PMCID:PMC7099601

[52] Liu Y,Yang M.Exosomes from hypoxic pretreated ADSCs attenuate ultraviolet light-induced skin injury via GLRX5 delivery and ferroptosis inhibition.Photochem Photobiol Sci2024;23:55-63

[53] Wang Y,Song S.Evaluation of the effect of exosomes from adipose derived stem cells on changes in GSH/ROS levels during skin photoaging.Photodermatol Photoimmunol Photomed2025;41:e70009

[54] Gao W,Yuan L,Wang YS.Long non-coding RNA H19-overexpressing exosomes ameliorate UVB-induced photoaging by upregulating SIRT1 via sponging miR-138.Photochem Photobiol2023;99:1456-67

[55] Wang T,Baskys A.MSC-derived exosomes protect against oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system.Biomaterials2020;257:120264

[56] Wu P,Han X.HucMSC exosome-delivered 14-3-3ζ alleviates ultraviolet radiation-induced photodamage via SIRT1 pathway modulation.Aging2021;13:11542-63 PMCID:PMC8109102

[57] Zhang Y,Yao A.Circ_0011129 encapsulated by the small extracellular vesicles derived from human stem cells ameliorate skin photoaging.Int J Mol Sci2022;23:15390 PMCID:PMC9739284

[58] Wu J,Wu Y.The crosstalk between exosomes and ferroptosis: a review.Cell Death Discov2024;10:170 PMCID:PMC11004161

[59] Santer L,Thum T.Circular RNAs: a novel class of functional RNA molecules with a therapeutic perspective.Mol Ther2019;27:1350-63 PMCID:PMC6697450

[60] Holdt LM,Teupser D.Circular RNAs as therapeutic agents and targets.Front Physiol2018;9:1262 PMCID:PMC6189416

[61] Zhang XO,Zhang Y.Diverse alternative back-splicing and alternative splicing landscape of circular RNAs.Genome Res2016;26:1277-87 PMCID:PMC5052039

[62] Jeck WR,Wang K.Circular RNAs are abundant, conserved, and associated with ALU repeats.RNA2013;19:141-57 PMCID:PMC3543092

[63] Hansen TB,Clausen BH.Natural RNA circles function as efficient microRNA sponges.Nature2013;495:384-8

[64] Li Y,Bao C.Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis.Cell Res2015;25:981-4 PMCID:PMC4528056

[65] Han Z,Guo Z.Circular RNAs and their role in exosomes.Front Oncol2022;12:848341 PMCID:PMC9096127

[66] Tenchov R,Wang X,Chen CA.Exosomes-nature’s lipid nanoparticles, a rising star in drug delivery and diagnostics.ACS Nano2022;16:17802-46 PMCID:PMC9706680

[67] Kalluri R.The biology, function, and biomedical applications of exosomes.Science2020;367:eaau6977 PMCID:PMC7717626

[68] 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

[69] Baldarelli RM, Smith CL, Ringwald M, Richardson JE, Bult CJ; Mouse Genome Informatics Group. Mouse Genome Informatics: an integrated knowledgebase system for the laboratory mouse. Genetics. 2024;227:iyae031. PMCID:PMC11075557

[70] He GN,Wang S,Zhang TH.Ketamine induces ferroptosis of liver cancer cells by targeting lncRNA PVT1/miR-214-3p/GPX4.Drug Des Devel Ther2021;15:3965-78 PMCID:PMC8458041

[71] Hou Y,Yu S.Metformin induces ferroptosis by targeting miR-324-3p/GPX4 axis in breast cancer.Acta Biochim Biophys Sin2021;53:333-41

[72] Ding C,Zheng J.miR-182-5p and miR-378a-3p regulate ferroptosis in I/R-induced renal injury.Cell Death Dis2020;11:929 PMCID:PMC7595188

[73] Dixon SJ.The cell biology of ferroptosis.Nat Rev Mol Cell Biol2024;25:424-42 PMCID:PMC12187608

[74] Alves F,Nguyen TPM,Ayton S.In defence of ferroptosis.Signal Transduct Target Ther2025;10:2 PMCID:PMC11696223

[75] Zhang Y,Nie G.3D-cultured hADSCs-derived exosomes deliver circ_0011129 to synergistically attenuate skin photoaging.Front Genet2025;16:1627472 PMCID:PMC12441608

[76] Noronha NC,Caliári-Oliveira C.Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies.Stem Cell Res Ther2019;10:131 PMCID:PMC6498654

[77] Zhang M,Liu L.Engineered exosomes from different sources for cancer-targeted therapy.Signal Transduct Target Ther2023;8:124 PMCID:PMC10017761

[78] Hackel A,Bruderek K,Brandau S.Immunological priming of mesenchymal stromal/stem cells and their extracellular vesicles augments their therapeutic benefits in experimental graft-versus-host disease via engagement of PD-1 ligands.Front Immunol2023;14:1078551 PMCID:PMC9978482

[79] Yang R,Cui S,Zhang T.IFN-γ promoted exosomes from mesenchymal stem cells to attenuate colitis via miR-125a and miR-125b.Cell Death Dis2020;11:603 PMCID:PMC7393506

[80] Chen YH,Hou J.Mesenchymal stem cell-derived exosomes induced by IL-1β attenuate urethral stricture through Let-7c/PAK1/NF-κB-regulated macrophage M2 polarization.J Inflamm Res2021;14:3217-29 PMCID:PMC8286124

[81] Vu DM,Nguyen TH.Effects of extracellular vesicles secreted by TGFβ-stimulated umbilical cord mesenchymal stem cells on skin fibroblasts by promoting fibroblast migration and ECM protein production.Biomedicines2022;10:1810 PMCID:PMC9405311

[82] 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

[83] Işıldar B,Koyutürk M.Preconditioning of human umbilical cord mesenchymal stem cells with a histone deacetylase inhibitor: valproic acid.Balkan Med J2024;41:369-76 PMCID:PMC11588919

[84] Rajendran RL,Oh JM,Ahn BC.Engineering three-dimensional spheroid culture for enrichment of proangiogenic miRNAs in umbilical cord mesenchymal stem cells and promotion of angiogenesis.ACS Omega2024;9:40358-67 PMCID:PMC11447852

[85] Rovere M,Arnaldi P,Gentili C.Spheroid size influences cellular senescence and angiogenic potential of mesenchymal stromal cell-derived soluble factors and extracellular vesicles.Front Bioeng Biotechnol2023;11:1297644 PMCID:PMC10756914

[86] Song Y,Tian W,Ye L.Optimizing therapeutic outcomes: preconditioning strategies for MSC-derived extracellular vesicles.Front Pharmacol2025;16:1509418 PMCID:PMC11847897

[87] Han Y,Dutta S.Overview and update on methods for cargo loading into extracellular vesicles.Processes2021;9:356 PMCID:PMC8096148

[88] Almeida C,Dias F,Medeiros R.Extracellular vesicles as potential therapeutic messengers in cancer management.Biology2023;12:665 PMCID:PMC10215130

[89] Liu Q,Pan X.Targeted therapy using engineered extracellular vesicles: principles and strategies for membrane modification.J Nanobiotechnology2023;21:334 PMCID:PMC10505332

[90] Haney MJ,Zhao Y.Exosomes as drug delivery vehicles for Parkinson’s disease therapy.J Control Release2015;207:18-30 PMCID:PMC4430381

[91] Kooijmans SAA,Braeckmans K.Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles.J Control Release2013;172:229-38

[92] Haraszti RA,Didiot MC.Optimized cholesterol-siRNA chemistry improves productive loading onto extracellular vesicles.Mol Ther2018;26:1973-82 PMCID:PMC6094392

[93] Huang T,Kuramochi A.Surface modulation of extracellular vesicles with cell-penetrating peptide-conjugated lipids for improvement of intracellular delivery to endothelial cells.Regen Ther2023;22:90-8 PMCID:PMC9842955

[94] 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

[95] Delcayre A,Sperinde J.Exosome Display technology: applications to the development of new diagnostics and therapeutics.Blood Cells Mol Dis2005;35:158-68

[96] Ohno S,Sudo K.Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells.Mol Ther2013;21:185-91 PMCID:PMC3538304

[97] Zhou Y,Liu M.Tumor-specific delivery of KRAS siRNA with iRGD-exosomes efficiently inhibits tumor growth.ExRNA2019;1:28

[98] Choi H,Park C.Targeted delivery of exosomes armed with anti-cancer therapeutics.Membranes2022;12:85 PMCID:PMC8782002

[99] Morishita M,Nishikawa M.Quantitative analysis of tissue distribution of the B16BL6-derived exosomes using a streptavidin-lactadherin fusion protein and iodine-125-labeled biotin derivative after intravenous injection in mice.J Pharm Sci2015;104:705-13

[100] Susa F,Dumontel B,Cauda V.Engineered extracellular vesicles as a reliable tool in cancer nanomedicine.Cancers2019;11:1979 PMCID:PMC6966613

[101] Liang Y,Lu J.Engineering exosomes for targeted drug delivery.Theranostics2021;11:3183-95 PMCID:PMC7847680

[102] Srivatsav AT.The emerging world of membrane vesicles: functional relevance, theranostic avenues and tools for investigating membrane function.Front Mol Biosci2021;8:640355 PMCID:PMC8101706

[103] Williams AC.Penetration enhancers.Adv Drug Deliv Rev2004;56:603-18

[104] Ramadon D,Courtenay AJ.Enhancement strategies for transdermal drug delivery systems: current trends and applications.Drug Deliv Transl Res2022;12:758-91 PMCID:PMC7817074

[105] Hmingthansanga V,Banerjee S,Velayutham R.Improved topical drug delivery: role of permeation enhancers and advanced approaches.Pharmaceutics2022;14:2818 PMCID:PMC9785322

[106] Haykal D,Garibyan L,Gold M.Exosomes in cosmetic dermatology: a review of benefits and challenges.J Drugs Dermatol2025;24:12-8

[107] Yuan F,Wang Z.Preserving extracellular vesicles for biomedical applications: consideration of storage stability before and after isolation.Drug Deliv2021;28:1501-9 PMCID:PMC8281093

[108] Yu H,Yang L.MSC-derived exosomes injectable hyaluronic acid hydrogel for enhanced chronic wound healing.J Control Release2025;385:113985

[109] Prasai A,Jupiter D,El Ayadi A.Role of exosomes in dermal wound healing: a systematic review.J Invest Dermatol2022;142:662-78.e8 PMCID:PMC9400548

[110] Di Rocco G, Baldari S, Toietta G. Towards therapeutic delivery of extracellular vesicles: strategies for in vivo tracking and biodistribution analysis.Stem Cells Int2016;2016:5029619 PMCID:PMC5141304

[111] Smyth T,Payton NM.Surface functionalization of exosomes using click chemistry.Bioconjug Chem2014;25:1777-84 PMCID:PMC4198107

[112] Van Deun J,Sormunen R.The impact of disparate isolation methods for extracellular vesicles on downstream RNA profiling.J Extracell Vesicles2014;3:24858 PMCID:PMC4169610

[113] Böing AN,Grootemaat AE,Sturk A.Single-step isolation of extracellular vesicles by size-exclusion chromatography.J Extracell Vesicles2014;3:23430 PMCID:PMC4159761

[114] Visan KS,Ham S.Comparative analysis of tangential flow filtration and ultracentrifugation, both combined with subsequent size exclusion chromatography, for the isolation of small extracellular vesicles.J Extracell Vesicles2022;11:e12266 PMCID:PMC9486818

[115] Busatto S,Ticer T.Tangential flow filtration for highly efficient concentration of extracellular vesicles from large volumes of fluid.Cells2018;7:273 PMCID:PMC6315734

[116] Kapoor KS,Arian KA.High throughput and rapid isolation of extracellular vesicles and exosomes with purity using size exclusion liquid chromatography.Bioact Mater2024;40:683-95 PMCID:PMC11407901

[117] Kawai-Harada Y,Harada M.Scalable isolation of surface-engineered extracellular vesicles and separation of free proteins via tangential flow filtration and size exclusion chromatography (TFF-SEC).BMC Methods2024;1:9

[118] Haraszti RA,Stoppato M.Exosomes produced from 3D cultures of MSCs by tangential flow filtration show higher yield and improved activity.Mol Ther2018;26:2838-47 PMCID:PMC6277553

[119] Sharma A,Nandy A.Insight into the functional dynamics and challenges of exosomes in pharmaceutical innovation and precision medicine.Pharmaceutics2024;16:709 PMCID:PMC11206934

[120] Wang CK,Lee CH.Regulation of exosomes as biologic medicines: regulatory challenges faced in exosome development and manufacturing processes.Clin Transl Sci2024;17:e13904 PMCID:PMC11307316

[121] Baharlooi H,Salehi Z.Mesenchymal stem cell-derived exosomes: a promising therapeutic ace card to address autoimmune diseases.Int J Stem Cells2020;13:13-23 PMCID:PMC7119210

[122] Imai T,Nishikawa M.Macrophage-dependent clearance of systemically administered B16BL6-derived exosomes from the blood circulation in mice.J Extracell Vesicles2015;4:26238 PMCID:PMC4323410

[123] Wiklander OP,O’Loughlin A.Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting.J Extracell Vesicles2015;4:26316 PMCID:PMC4405624

[124] Gupta D,Wood MJA.Biodistribution of therapeutic extracellular vesicles.Extracell Vesicles Circ Nucl Acids2023;4:170-90 PMCID:PMC11648525

[125] Lyu C,Sun Z,Wang Q.Roles of exosomes in immunotherapy for solid cancers.Cell Death Dis2024;15:106 PMCID:PMC10834551

[126] Vakhshiteh F,Ostad SN.Mesenchymal stem cell exosomes: a two-edged sword in cancer therapy.Int J Nanomedicine2019;14:2847-59 PMCID:PMC6488158

[127] Lin Z,Xu Y,Li Z.Mesenchymal stem cell-derived exosomes in cancer therapy resistance: recent advances and therapeutic potential.Mol Cancer2022;21:179 PMCID:PMC9468526

[128] Welsh JA,Bettin BA.Towards defining reference materials for measuring extracellular vesicle refractive index, epitope abundance, size and concentration.J Extracell Vesicles2020;9:1816641 PMCID:PMC7534292

[129] Domaszewska-Szostek A,Polak A.Effectiveness of extracellular vesicle application in skin aging treatment and regeneration: do we have enough evidence from clinical trials?.Int J Mol Sci2025;26:2354 PMCID:PMC11899913

[130] Park GH,Seok J.Efficacy of combined treatment with human adipose tissue stem cell-derived exosome-containing solution and microneedling for facial skin aging: a 12-week prospective, randomized, split-face study.J Cosmet Dermatol2023;22:3418-26

[131] Kwon HH,Lee J.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 Venereol2020;100:adv00310 PMCID:PMC9309822

[132] Wan J,Cartier H.A prospective study of exosome therapy for androgenetic alopecia.Aesthetic Plast Surg2025;49:3151-6

[133] Hu L,Zhou X.Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts.Sci Rep2016;6:32993 PMCID:PMC5018733

[134] Lee JH,Kim H.Adipose tissue-derived mesenchymal stem cell-derived exosomes promote wound healing and tissue regeneration.Int J Mol Sci2023;24:10434 PMCID:PMC10341478

[135] Qiu Z,Zhang Y,Deng B.Human umbilical cord mesenchymal stem cell-derived exosomal miR-335-5p attenuates the inflammation and tubular epithelial-myofibroblast transdifferentiation of renal tubular epithelial cells by reducing ADAM19 protein levels.Stem Cell Res Ther2022;13:373 PMCID:PMC9330665

[136] Wang XY,Yu ZP.Human amniotic stem cells-derived exosmal miR-181a-5p and miR-199a inhibit melanogenesis and promote melanosome degradation in skin hyperpigmentation, respectively.Stem Cell Res Ther2021;12:501 PMCID:PMC8431893

[137] Rodriguez C,Chemali M.Medicalized aesthetic uses of exosomes and cell culture-conditioned media: opening an advanced care era for biologically inspired cutaneous prejuvenation and rejuvenation.Cosmetics2024;11:154

[138] Tienda-Vázquez MA,Márquez-Arteaga EM.Exosomes: a promising strategy for repair, regeneration and treatment of skin disorders.Cells2023;12:1625 PMCID:PMC10296902

[139] Wang M,Huang J.Skin cell-derived extracellular vesicles: a promising therapeutic strategy for cutaneous injury.Burns Trauma2022;10:tkac037 PMCID:PMC9580071

[140] Nasiri G,Alizadeh A,Tayebi L.Shedding light on the role of keratinocyte-derived extracellular vesicles on skin-homing cells.Stem Cell Res Ther2020;11:421 PMCID:PMC7523352

[141] Pinto H.Exosomes in the real world of medical aesthetics: a review.Aesthetic Plast Surg2024;48:2513-27