Extracellular vesicles in burn injury: roles, mechanisms, and applications

Abstract

The morbidity and mortality rate from burn injuries is substantial, and patients might suffer irreparable harm from the several pathophysiological processes that severe burns cause, including metabolic alterations, distributive shock, and inflammatory responses. Prevention of infections, reduction of inflammation, alleviation of pain, and regulation of growth factors are all essential components of burn wound care, yet there are still major challenges. Multiple biological activities rely on extracellular vesicles (EVs), which are lipid bilayer vesicles released by a wide range of cell types (including prokaryotes, plant cells, and mammals). Among these processes are immunomodulation, neovascularization, and cell survival. Due to their rich composition, EVs may carry a variety of active substances, including nucleic acids and proteins, and hence play a pivotal role in many subcellular levels during wound healing. In addition, EVs may be found in a variety of burn damage patients’ biofluids, making them potential new biomarkers for tracking the efficacy of treatments and making prognoses assumptions. An overview of the biological functions of EVs and the ways in which they alleviate burn injuries is provided in this paper. Additionally, we cover the likelihood of EVs being used in burn wound treatment in the future. This study aims to inspire and direct future comprehensive research on the use of EVs in burn wound healing, introduce a novel treatment for burn wounds, and serve as a resource for anybody interested in using EVs for clinical wound healing.

Keywords

Extracellular vesicles / Different sources / Biomarker / Burn injury / Wound healing

References

[1] Greenhalgh DG.Management of Burns. N Engl J Med. 2019; 380: 2349-59. https://doi.org/10.1056/NEJMra1807442.

[2] Opriessnig E, Luze H, Smolle C, Draschl A, Zrim R, Giretzlehner M, et al. Epidemiology of burn injury and the ideal dressing in global burn care-regional differences explored. Burns. 2023; 49: 1-14. https://doi.org/10.1016/j.burns.2022.06.018.

[3] Smolle C, Cambiaso-Daniel J, Forbes AA, Wurzer P, Hundeshagen G, Branski LK, et al. Recent trends in burn epidemiology worldwide: a systematic review. Burns. 2017; 43: 249-57. https://doi.org/10.1016/j.burns.2016.08.013.

[4] Prasetyo AT, Hasibuan LY, Arsyad M. Pedicled abdominal skin flap technique for fingers salvaging and reconstruction in a complex palmar hand burn injury: a case report. Int J Surg Case Rep. 2024; 114: 109199. https://doi.org/10.1016/j.ijscr.2023.109199.

[5] Levin NJ, Erben Y, Li Y, Brigham TJ, Bruce AJ. A systematic review and meta-analysis comparing burn healing outcomes between silver sulfadiazine and Aloe vera. Cureus. 2022; 14: e30815. https://doi.org/10.7759/cureus.30815.

[6] Hill AF.Extracellular vesicles and neurodegenerative diseases. J Neurosci. 2019; 39: 9269-73. https://doi.org/10.1523/JNEUROSCI.0147-18.2019.

[7] Marar C, Starich B, Wirtz D. Extracellular vesicles in immunomodulation and tumor progression. Nat Immunol. 2021; 22: 560-70. https://doi.org/10.1038/s41590-021-00899-0.

[8] Zhang W, Bai X, Zhao B, Li Y, Zhang Y, Li Z, et al. Cell-free therapy based on adipose tissue stem cell-derived exosomes promotes wound healing via the PI3K/Akt signaling pathway. Exp Cell Res. 2018; 370: 333-42. https://doi.org/10.1016/j.yexcr.2018.06.035.

[9] Li B, Luan S, Chen J, Zhou Y, Wang T, Li Z, et al. The MSC-derived Exosomal lncRNA H19 promotes wound healing in diabetic foot ulcers by upregulating PTEN via MicroRNA-152-3p. Mol Ther Nucleic Acids. 2020; 19: 814-26. https://doi.org/10.1016/j.omtn.2019.11.034.

[10] Liu W, Zu L, Wang S, Li J, Fei X, Geng M, et al. Tailored biomedical materials for wound healing. Burns Trauma. 2023; 11: tkad040. https://doi.org/10.1093/burnst/tkad040.

[11] Strbo N, Yin N, Stojadinovic O. Innate and adaptive immune responses in wound epithelialization. Adv Wound Care (New Rochelle). 2014; 3: 492-501. https://doi.org/10.1089/wound.2012.0435.

[12] Roefs MT, Sluijter JPG, Vader P. Extracellular vesicle-associated proteins in tissue repair. Trends Cell Biol. 2020; 30: 990-1013. https://doi.org/10.1016/j.tcb.2020.09.009.

[13] Bian D, Wu Y, Song G, Azizi R, Zamani A. The application of mesenchymal stromal cells (MSCs) and their derivative exosome in skin wound healing: a comprehensive review. Stem Cell Res Ther. 2022; 13: 24. https://doi.org/10.1186/s13287-021-02697-9.

[14] Tienda-Vazquez MA, Hanel JM, Marquez-Arteaga EM, Salgado-Alvarez AP, Scheckhuber CQ, Alanis-Gomez JR, et al. Exosomes: a promising strategy for repair, regeneration and treatment of skin disorders. Cells. 2023; 12: 1625. https://doi.org/10.3390/cells12121625.

[15] Lou P, Liu S, Xu X, Pan C, Lu Y, Liu J. Extracellular vesicle-based therapeutics for the regeneration of chronic wounds: current knowledge and future perspectives. Acta Biomater. 2021; 119: 42-56. https://doi.org/10.1016/j.actbio.2020.11.001.

[16] Yan Z, Zhang T, Wang Y, Xiao S, Gao J. Extracellular vesicle biopotentiated hydrogels for diabetic wound healing: the art of living nanomaterials combined with soft scaffolds. Mater Today Bio. 2023; 23: 100810. https://doi.org/10.1016/j.mtbio.2023.100810.

[17] Jia Q, Zhao H, Wang Y, Cen Y, Zhang Z. Mechanisms and applications of adipose-derived stem cell-extracellular vesicles in the inflammation of wound healing. Front Immunol. 2023; 14: 1214757. https://doi.org/10.3389/fimmu.2023.1214757.

[18] Jiang M, Jiang X, Li H, Zhang C, Zhang Z, Wu C, et al. The role of mesenchymal stem cell-derived EVs in diabetic wound healing. Front Immunol. 2023; 14: 1136098. https://doi.org/10.3389/fimmu.2023.1136098.

[19] Ju C, Liu D. Exosomal microRNAs from mesenchymal stem cells: novel therapeutic effect in wound healing. Tissue Eng Regen Med. 2023; 20: 647-60. https://doi.org/10.1007/s13770-023-00542-z.

[20] Yang B, Lin Y, Huang Y, Zhu N, Shen YQ. Extracellular vesicles modulate key signalling pathways in refractory wound healing. Burns Trauma. 2023; 11: tkad039. https://doi.org/10.1093/burnst/tkad039.

[21] Qin X, He J, Wang X, Wang J, Yang R, Chen X. The functions and clinical application potential of exosomes derived from mesenchymal stem cells on wound repair: a review of recent research advances. Front Immunol. 2023; 14: 1256687. https://doi.org/10.3389/fimmu.2023.1256687.

[22] Wang M, Wu P, Huang J, Liu W, Qian H, Sun Y, et al. Skin cell-derived extracellular vesicles: a promising therapeutic strategy for cutaneous injury. Burns Trauma. 2022; 10: tkac037. https://doi.org/10.1093/burnst/tkac037.

[23] Jeschke MG, van Baar ME, Choudhry MA, Chung KK, Gibran NS, Logsetty S. Burn injury. Nat Rev Dis Primers. 2020; 6: 11. https://doi.org/10.1038/s41572-020-0145-5.

[24] Yildiz M, Sarpdagi Y, Okuyar M, Yildiz M, Ciftci N, Elkoca A, et al. Segmentation and classification of skin burn images with artificial intelligence: development of a mobile application. Burns. 2024; 50: 966-79. https://doi.org/10.1016/j.burns.2024.01.007.

[25] Stoica AE, Chircov C, Grumezescu AM. Hydrogel dressings for the treatment of burn wounds: an up-to-date overview. Materials (Basel). 2020; 13: 2853. https://doi.org/10.3390/ma13122853.

[26] Abazari M, Ghaffari A, Rashidzadeh H, Badeleh SM, Maleki Y. A systematic review on classification, identification, and healing process of burn wound healing. Int J Low Extrem Wounds. 2022; 21: 18-30. https://doi.org/10.1177/1534734620924857.

[27] Sierra C, Moreno M, Garcia-Ruiz JC. The physiology of hemostasis. Blood Coagul Fibrinolysis. 2022; 33: S1-2. https://doi.org/10.1097/MBC.0000000000001099.

[28] Ma Y, Liu Z, Miao L, Jiang X, Ruan H, Xuan R, et al. Mechanisms underlying pathological scarring by fibroblasts during wound healing. Int Wound J. 2023; 20: 2190-206. https://doi.org/10.1111/iwj.14097.

[29] Rousselle P, Braye F, Dayan G.Re-epithelialization of adult skin wounds: cellular mechanisms and therapeutic strategies. Adv Drug Deliv Rev. 2019; 146: 344-65. https://doi.org/10.1016/j.addr.2018.06.019.

[30] Sheridan RL.Management of burns. Surg Clin North Am. 2014; 94: xv-xvi. https://doi.org/10.1016/j.suc.2014.06.001.

[31] Zacharevskij E, Baranauskas G, Varkalys K, Rimdeika R, Kubilius D. Comparison of non-surgical methods for the treatment of deep partial thickness skin burns of the hand. Burns. 2018; 44: 445-52. https://doi.org/10.1016/j.burns.2017.08.002.

[32] Zhang M, Xing J, Zhong Y, Zhang T, Liu X, Xing D. Advanced function, design and application of skin substitutes for skin regeneration. Mater Today Bio. 2024; 24: 100918. https://doi.org/10.1016/j.mtbio.2023.100918.

[33] Buote NJ. Updates in wound management and dressings. Vet Clin North Am Small Anim Pract. 2022; 52: 289-315. https://doi.org/10.1016/j.cvsm.2021.12.001.

[34] Zheng X, Li X, Chen T, Chang F, Ji S, Hu X, et al. Effect of the orientation of microskin on the survival rate of transplantation and improving the method. Int J Clin Exp Pathol. 2021; 14: 186-95.

[35] Luo Y, Yi X, Liang T, Jiang S, He R, Hu Y, et al. Autograft microskin combined with adipose-derived stem cell enhances wound healing in a full-thickness skin defect mouse model. Stem Cell Res Ther. 2019; 10: 279. https://doi.org/10.1186/s13287-019-1389-4.

[36] Fang Z, Li J, Wang K, He T, Wang H, Xie S, et al. Autologous scar-related tissue combined with skin grafting for reconstructing large area burn scar. J Investig Surg. 2022; 35: 1779-88. https://doi.org/10.1080/08941939.2022.2101164.

[37] Khan AZ, Utheim TP, Byholt M, Fiabema T, Sylvester-Jensen HC, Tonseth KA. Skin grafting. Tidsskr Nor Laegeforen. 2022; 142: 10.4045. https://doi.org/10.4045/tidsskr.21.0671.

[38] Richters CD, Hoekstra MJ, du Pont JS, Kreis RW, Kamperdijk EW. Immunology of skin transplantation. Clin Dermatol. 2005; 23: 338-42. https://doi.org/10.1016/j.clindermatol.2004.07.022.

[39] Maleki A, He J, Bochani S, Nosrati V, Shahbazi MA, Guo B. Multifunctional photoactive hydrogels for wound healing acceleration. ACS Nano. 2021; 15: 18895-930. https://doi.org/10.1021/acsnano.1c08334.

[40] Wang M, Xu X, Lei X, Tan J, Xie H. Mesenchymal stem cell-based therapy for burn wound healing. Burns Trauma. 2021; 9: tkab002. https://doi.org/10.1093/burnst/tkab002.

[41] Tang W. Challenges and advances in stem cell therapy. Biosci Trends. 2019; 13: 286. https://doi.org/10.5582/bst.2019.01241.

[42] Wu X, Huang D, Xu Y, Chen G, Zhao Y. Microfluidic Templated stem cell spheroid microneedles for diabetic wound treatment. Adv Mater. 2023; 35: e2301064. https://doi.org/10.1002/adma.202301064.

[43] Cocozza F, Grisard E, Martin-Jaular L, Mathieu M, Thery C. SnapShot: extracellular vesicles. Cell. 2020; 182: 262-262.e1. https://doi.org/10.1016/j.cell.2020.04.054.

[44] Welsh JA, Goberdhan DCI, O’Driscoll L, Buzas EI, Blenkiron C, Bussolati B, et al. Minimal information for studies of extracellular vesicles (MISEV2023): from basic to advanced approaches. J Extracell Vesicles. 2024; 13: e12404. https://doi.org/10.1002/jev2.12404.

[45] van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018; 19: 213-28. https://doi.org/10.1038/nrm.2017.125.

[46] Pfeffer SR.Two Rabs for exosome release. Nat Cell Biol. 2010; 12: 3-4. https://doi.org/10.1038/ncb0110-3.

[47] Colombo M, Raposo G, Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014; 30: 255-89. https://doi.org/10.1146/annurev-cellbio-101512-122326.

[48] Xu M, Ji J, Jin D, Wu Y, Wu T, Lin R, et al. The biogenesis and secretion of exosomes and multivesicular bodies (MVBs): intercellular shuttles and implications in human diseases. Genes Dis. 2023; 10: 1894-907. https://doi.org/10.1016/j.gendis.2022.03.021.

[49] Wang X, Wu R, Zhai P, Liu Z, Xia R, Zhang Z, et al. Hypoxia promotes EV secretion by impairing lysosomal homeostasis in HNSCC through negative regulation of ATP6V1A by HIF-1alpha. J Extracell Vesicles. 2023; 12:e12310. https://doi.org/10.1002/jev2.12310.

[50] Lee TH, D’Asti E, Magnus N, Al-Nedawi K, Meehan B, Rak J. Microvesicles as mediators of intercellular communication in cancer-the emerging science of cellular ‘debris’. Semin Immunopathol. 2011; 33: 455-67. https://doi.org/10.1007/s00281-011-0250-3.

[51] Zhang X, Zhang H, Gu J, Zhang J, Shi H, Qian H, et al. Engineered extracellular vesicles for cancer therapy. Adv Mater. 2021; 33: e2005709. https://doi.org/10.1002/adma.202005709.

[52] Hugel B, Martinez MC, Kunzelmann C, Freyssinet JM. Membrane microparticles: two sides of the coin. Physiology (Bethesda). 2005; 20: 22-7.

[53] Zhao D, Tao W, Li S, Chen Y, Sun Y, He Z, et al. Apoptotic body-mediated intercellular delivery for enhanced drug penetration and whole tumor destruction. Sci Adv. 2021; 7:eabg0880. https://doi.org/10.1126/sciadv.abg0880.

[54] Jeppesen DK, Fenix AM, Franklin JL, Higginbotham JN, Zhang Q, Zimmerman LJ, et al. Reassessment of exosome composition. Cell. 2019; 177: 428-445.e18. https://doi.org/10.1016/j.cell.2019.02.029.

[55] Lai P, Weng J, Guo L, Chen X, Du X. Novel insights into MSC-EVs therapy for immune diseases. Biomark Res. 2019; 7: 6. https://doi.org/10.1186/s40364-019-0156-0.

[56] Harrell CR, Jovicic N, Djonov V, Arsenijevic N, Volarevic V. Mesenchymal stem cell-derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases. Cells. 2019; 8: 1605. https://doi.org/10.3390/cells8121605.

[57] Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020; 367: eaau6977. https://doi.org/10.1126/science.aau6977.

[58] Li A, Yu J, Kim H, Wolfgang CL, Canto MI, Hruban RH, et al. MicroRNA array analysis finds elevated serum miR-1290 accurately distinguishes patients with low-stage pancreatic cancer from healthy and disease controls. Clin Cancer Res. 2013; 19: 3600-10. https://doi.org/10.1158/1078-0432.CCR-12-3092.

[59] Pironti G, Strachan RT, Abraham D, Mon-Wei Yu S, Chen M, Chen W, et al. Circulating exosomes induced by cardiac pressure overload contain functional angiotensin II type 1 receptors. Circulation. 2015; 131: 2120-30. https://doi.org/10.1161/CIRCULATIONAHA.115.015687.

[60] Pourali G, Zafari N, Fiuji H, Batra J, Nazari E, Khazaei M, et al. Extracellular vesicles: emerging mediators of cell communication in gastrointestinal cancers exhibiting metabolic abnormalities. Cytokine Growth Factor Rev. 2023; 73: 101-13. https://doi.org/10.1016/j.cytogfr.2023.08.001.

[61] Hansen AS, Jensen LS, Gammelgaard KR, Ryttersgaard KG, Krapp C, Just J, et al. T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy. J Extracell Vesicles. 2023; 12: e12350. https://doi.org/10.1002/jev2.12350.

[62] Batrakova EV, Kim MS. Using exosomes, naturally-equipped nanocarriers, for drug delivery. J Control Release. 2015; 219: 396-405. https://doi.org/10.1016/j.jconrel.2015.07.030.

[63] Hu L, Wang J, Zhou X, Xiong Z, Zhao J, Yu R, et al. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts. Sci Rep. 2016; 6: 32993. https://doi.org/10.1038/srep32993.

[64] Doyle LM, Wang MZ. Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells. 2019; 8: 727. https://doi.org/10.3390/cells8070727.

[65] Dalirfardouei R, Gholoobi A, Vahabian M, Mahdipour E, Afzaljavan F. Therapeutic role of extracellular vesicles derived from stem cells in cutaneous wound models: a systematic review. Life Sci. 2021; 273: 119271. https://doi.org/10.1016/j.lfs.2021.119271.

[66] Logozzi M, De Milito A, Lugini L, Borghi M, Calabro L, Spada M, et al. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS One. 2009; 4: e5219. https://doi.org/10.1371/journal.pone.0005219.

[67] Keller S, Ridinger J, Rupp AK, Janssen JW, Altevogt P. Body fluid derived exosomes as a novel template for clinical diagnostics. J Transl Med. 2011; 9: 86. https://doi.org/10.1186/1479-5876-9-86.

[68] Zhou L, Wang W, Wang F, Yang S, Hu J, Lu B, et al. Plasma-derived exosomal miR-15a-5p as a promising diagnostic biomarker for early detection of endometrial carcinoma. Mol Cancer. 2021; 20: 57. https://doi.org/10.1186/s12943-021-01352-4.

[69] Shin S, Park YH, Jung SH, Jang SH, Kim MY, Lee JY, et al. Urinary exosome microRNA signatures as a noninvasive prognostic biomarker for prostate cancer. NPJ Genom Med. 2021; 6: 45. https://doi.org/10.1038/s41525-021-00212-w.

[70] Guo X, Lv X, Ru Y, Zhou F, Wang N, Xi H, et al. Circulating Exosomal gastric cancer-associated long noncoding RNA1 as a biomarker for early detection and monitoring progression of gastric cancer: a multiphase study. JAMA Surg. 2020; 155: 572-9. https://doi.org/10.1001/jamasurg.2020.1133.

[71] Xie M, Yu T, Jing X, Ma L, Fan Y, Yang F, et al. Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation. Mol Cancer. 2020; 19: 112. https://doi.org/10.1186/s12943-020-01208-3.

[72] Deng C, Huo M, Chu H, Zhuang X, Deng G, Li W, et al. Exosome circATP8A1 induces macrophage M2 polarization by regulating the miR-1-3p/STAT6 axis to promote gastric cancer progression. Mol Cancer. 2024; 23: 49. https://doi.org/10.1186/s12943-024-01966-4.

[73] Ding J, Pan Y, Raj S, Schaffrick L, Wong J, Nguyen A, et al. Characteristics of serum exosomes after burn injury and dermal fibroblast regulation by exosomes in vitro. Cells. 2023; 12: 1738. https://doi.org/10.3390/cells12131738.

[74] Yang X, Chatterjee V, Zheng E, Reynolds A, Ma Y, Villalba N, et al. Burn injury-induced extracellular vesicle production and characteristics. Shock. 2022; 57: 228-42. https://doi.org/10.1097/SHK.0000000000001938.

[75] Willis ML, Mahung C, Wallet SM, Barnett A, Cairns BA, Coleman LG Jr, et al. Plasma extracellular vesicles released after severe burn injury modulate macrophage phenotype and function. J Leukoc Biol. 2022; 111: 33-49. https://doi.org/10.1002/JLB.3MIA0321-150RR.

[76] Wang A, Zheng N, Jia Q, Chen Y, Xu S. S100A9-containing serum exosomes obtained from patients with burn injuries promote myocardial cell pyroptosis through NLRP3. Exp Ther Med. 2022; 24: 646. https://doi.org/10.3892/etm.2022.11583.

[77] Wang A, Guo B, Jia Q, Chen YU, Gao X, Xu S. S100A9-containing serum exosomes of burn injury patients promote permeability of pulmonary microvascular endothelial cells. J Biosci. 2021; 46: 33. https://doi.org/10.1007/s12038-021-00151-9.

[78] Rohan CJ, Lohade RP, Brewer C, Travers JB. Platelet-activating factor and microvesicle particles as potential mediators for the toxicity associated with intoxicated thermal burn injury. Biofactors. 2022; 48: 1250-6. https://doi.org/10.1002/biof.1917.

[79] Li SJ, Cai ZW, Yang HF, Tang XD, Fang X, Qiu L, et al. A next-generation sequencing of plasma exosome-derived microRNAs and target gene analysis with a microarray database of thermally injured skins: identification of blood-to-tissue interactions at early burn stage. J Inflamm Res. 2021; 14: 6783-98. https://doi.org/10.2147/JIR.S343956.

[80] Dong M, Gao Y, Li M, Yang L. Altered expression of microRNAs in serum extracellular vesicles in rats with severe burns during shock stage. Curr Mol Med. 2021; 21: 665-74. https://doi.org/10.2174/1566524020666200712181644.

[81] Qin D, Yang W, Pan Z, Zhang Y, Li X, Lakshmanan S. Differential proteomics analysis of serum exosome in burn patients. Saudi J Biol Sci. 2020; 27: 2215-20. https://doi.org/10.1016/j.sjbs.2020.06.024.

[82] Coleman LG Jr, Maile R, Jones SW, Cairns BA, Crews FT. HMGB1/IL-1beta complexes in plasma microvesicles modulate immune responses to burn injury. PLoS One. 2018; 13: e0195335. https://doi.org/10.1371/journal.pone.0195335.

[83] Maile R, Willis ML, Herring LE, Prevatte A, Mahung C, Cairns B, et al. Burn injury induces Proinflammatory plasma extracellular vesicles that associate with length of hospital stay in women: CRP and SAA1 as potential prognostic indicators. Int J Mol Sci. 2021; 22: 10083. https://doi.org/10.3390/ijms221810083.

[84] Zhou J, Ding Y, Zhang Y, Zheng D, Yan L, Guo M, et al. Exosomes from bone marrow-derived mesenchymal stem cells facilitate corneal wound healing via regulating the p44/42 MAPK pathway. Graefes Arch Clin Exp Ophthalmol. 2023; 261: 723-34. https://doi.org/10.1007/s00417-022-05956-4.

[85] Sun X, Song W, Teng L, Huang Y, Liu J, Peng Y, et al. MiRNA 24-3p-rich exosomes functionalized DEGMA-modified hyaluronic acid hydrogels for corneal epithelial healing. Bioact Mater. 2023; 25: 640-56. https://doi.org/10.1016/j.bioactmat.2022.07.011.

[86] Wu H, He S, Zhang W, Huang Y, Zhang Q, Liu D. Administration of circRNA_0075932 shRNA exhibits a therapeutic effect on burn-associated infection in obese rats. Biochem Biophys Res Commun. 2022; 608: 82-9. https://doi.org/10.1016/j.bbrc.2022.03.145.

[87] Saccu G, Menchise V, Gai C, Bertolin M, Ferrari S, Giordano C, et al. Bone marrow mesenchymal stromal/stem cell-derived extracellular vesicles promote corneal wound repair by regulating inflammation and angiogenesis. Cells. 2022; 11: 3892. https://doi.org/10.3390/cells11233892.

[88] Liu J, Yan Z, Yang F, Huang Y, Yu Y, Zhou L, et al. Exosomes derived from human umbilical cord mesenchymal stem cells accelerate cutaneous wound healing by enhancing angiogenesis through delivering Angiopoietin-2. Stem Cell Rev Rep. 2021; 17: 305-17. https://doi.org/10.1007/s12015-020-09992-7.

[89] Zhang B, Shi Y, Gong A, Pan Z, Shi H, Yang H, et al. HucMSC exosome-delivered 14-3-3zeta orchestrates self-control of the Wnt response via modulation of YAP during cutaneous regeneration. Stem Cells. 2016; 34: 2485-500. https://doi.org/10.1002/stem.2432.

[90] Li X, Liu L, Yang J, Yu Y, Chai J, Wang L, et al. Exosome derived from human umbilical cord mesenchymal stem cell mediates MiR-181c attenuating burn-induced excessive inflammation. EBioMedicine. 2016; 8: 72-82. https://doi.org/10.1016/j.ebiom.2016.04.030.

[91] Rohan Ivari J, Mahdipour E. Adipose tissue versus stem cell-derived small extracellular vesicles to enhance the healing of acute burns. Regen Med. 2021; 16: 629-41. https://doi.org/10.2217/rme-2020-0199.

[92] Yan Y, Wu R, Bo Y, Zhang M, Chen Y, Wang X, et al. Induced pluripotent stem cells-derived microvesicles accelerate deep second-degree burn wound healing in mice through miR-16-5p-mediated promotion of keratinocytes migration. Theranostics. 2020; 10: 9970-83. https://doi.org/10.7150/thno.46639.

[93] Imam RA, Amer MM. Potential therapeutic role of microvesicles derived from mesenchymal stem cells and platelet-rich plasma in murine burn wound healing: scar regulation and antioxidant mechanism. Folia Morphol (Warsz). 2023; 82: 656-67. https://doi.org/10.5603/FM.a2022.0060.

[94] Liu JS, Du J, Cheng X, Zhang XZ, Li Y, Chen XL. Exosomal miR-451 from human umbilical cord mesenchymal stem cells attenuates burn-induced acute lung injury. J Chin Med Assoc. 2019; 82: 895-901. https://doi.org/10.1097/JCMA.0000000000000189.

[95] Liu J, Xing F, Fu Q, He B, Jia Z, Du J, et al. hUC-MSCs exosomal miR-451 alleviated acute lung injury by modulating macrophage M2 polarization via regulating MIF-PI3K-AKT signaling pathway. Environ Toxicol. 2022; 37: 2819-31. https://doi.org/10.1002/tox.23639.

[96] Mansilla E, Marin GH, Berges M, Scafatti S, Rivas J, Nunez A, et al. Cadaveric bone marrow mesenchymal stem cells: first experience treating a patient with large severe burns. Burns Trauma. 2015; 3: 17. https://doi.org/10.1186/s41038-015-0018-4.

[97] Rasulov MF, Vasilchenkov AV, Onishchenko NA, Krasheninnikov ME, Kravchenko VI, Gorshenin TL, et al. First experience of the use bone marrow mesenchymal stem cells for the treatment of a patient with deep skin burns. Bull Exp Biol Med. 2005; 139: 141-4. https://doi.org/10.1007/s10517-005-0232-3.

[98] Farabi B, Roster K, Hirani R, Tepper K, Atak MF, Safai B. The efficacy of stem cells in wound healing: a systematic review. Int J Mol Sci. 2024; 25: 3006. https://doi.org/10.3390/ijms25053006.

[99] Zhou C, Zhang B, Yang Y, Jiang Q, Li T, Gong J, et al. Stem cell-derived exosomes: emerging therapeutic opportunities for wound healing. Stem Cell Res Ther. 2023; 14: 107. https://doi.org/10.1186/s13287-023-03345-0.

[100] Gnecchi M, Danieli P, Malpasso G, Ciuffreda MC. Paracrine mechanisms of mesenchymal stem cells in tissue repair. Methods Mol Biol. 2016; 1416: 123-46. https://doi.org/10.1007/978-1-4939-3584-0_7.

[101] Hu P, Yang Q, Wang Q, Shi C, Wang D, Armato U, et al. Mesenchymal stromal cells-exosomes: a promising cell-free therapeutic tool for wound healing and cutaneous regeneration. Burns Trauma. 2019; 7: 38. https://doi.org/10.1186/s41038-019-0178-8.

[102] Kucharzewski M, Rojczyk E, Wilemska-Kucharzewska K, Wilk R, Hudecki J, Los MJ. Novel trends in application of stem cells in skin wound healing. Eur J Pharmacol. 2019; 843: 307-15. https://doi.org/10.1016/j.ejphar.2018.12.012.

[103] Broughton G 2nd, Janis JE, Attinger CE. Wound healing: an overview. Plast Reconstr Surg. 2006; 117: 1e-S-32e-S. https://doi.org/10.1097/01.prs.0000222562.60260.f9.

[104] Galkowska H, Wojewodzka U, Olszewski WL. Chemokines, cytokines, and growth factors in keratinocytes and dermal endothelial cells in the margin of chronic diabetic foot ulcers. Wound Repair Regen. 2006; 14: 558-65. https://doi.org/10.1111/j.1743-6109.2006.00155.x.

[105] Hu ZC, Chen D, Guo D, Liang YY, Zhang J, Zhu JY, et al. Randomized clinical trial of autologous skin cell suspension combined with skin grafting for chronic wounds. Br J Surg. 2015; 102: e117-23. https://doi.org/10.1002/bjs.9688.

[106] Bo Y, Yang L, Liu B, Tian G, Li C, Zhang L, et al. Exosomes from human induced pluripotent stem cells-derived keratinocytes accelerate burn wound healing through miR-762 mediated promotion of keratinocytes and endothelial cells migration. J Nanobiotechnology. 2022; 20: 291. https://doi.org/10.1186/s12951-022-01504-8.

[107] Cui HS, Joo SY, Lee SY, Cho YS, Kim DH, Seo CH. Effect of hypertrophic scar fibroblast-derived exosomes on keratinocytes of normal human skin. Int J Mol Sci. 2023; 24: 6132. https://doi.org/10.3390/ijms24076132.

[108] Rana S, Yue S, Stadel D, Zoller M. Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. Int J Biochem Cell Biol. 2012; 44: 1574-84. https://doi.org/10.1016/j.biocel.2012.06.018.

[109] Kamerkar S, LeBleu VS, Sugimoto H, Yang S, Ruivo CF, Melo SA, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature. 2017; 546: 498-503. https://doi.org/10.1038/nature22341.

[110] Talmi YP, Sigler L, Inge E, Finkelstein Y, Zohar Y. Antibacterial properties of human amniotic membranes. Placenta. 1991; 12: 285-8. https://doi.org/10.1016/0143-4004(91)90010-D.

[111] Solomon A, Rosenblatt M, Monroy D, Ji Z, Pflugfelder SC, Tseng SC. Suppression of interleukin 1alpha and interleukin 1beta in human limbal epithelial cells cultured on the amniotic membrane stromal matrix. Br J Ophthalmol. 2001; 85: 444-9. https://doi.org/10.1136/bjo.85.4.444.

[112] Koizumi NJ, Inatomi TJ, Sotozono CJ, Fullwood NJ, Quantock AJ, Kinoshita S. Growth factor mRNA and protein in preserved human amniotic membrane. Curr Eye Res. 2000; 20: 173-7. https://doi.org/10.1076/0271-3683(200003)2031-9FT173.

[113] Shayan Asl N, Nejat F, Mohammadi P, Nekoukar A, Hesam S, Ebrahimi M, et al. Amniotic membrane extract eye drop promotes Limbal stem cell proliferation and corneal epithelium healing. Cell J. 2019; 20: 459-68. https://doi.org/10.22074/cellj.2019.5423.

[114] Hu S, Wang Z, Jin C, Chen Q, Fang Y, Jin J, et al. Human amniotic epithelial cell-derived extracellular vesicles provide an extracellular matrix-based microenvironment for corneal injury repair. J Tissue Eng. 2022; 13: 20417314221122123. https://doi.org/10.1177/20417314221122123.

[115] Wu Y, Hong P, Liu P, Zhang Q, Zhang Y, Yang B, et al. Lipoaspirate fluid derived factors and extracellular vesicles accelerate wound healing in a rat burn model. Front Bioeng Biotechnol. 2023; 11: 1185251. https://doi.org/10.3389/fbioe.2023.1185251.

[116] Kim J, Li S, Zhang S, Wang J. Plant-derived exosome-like nanoparticles and their therapeutic activities. Asian J Pharm Sci. 2022; 17: 53-69. https://doi.org/10.1016/j.ajps.2021.05.006.

[117] Sahin F, Kocak P, Gunes MY, Ozkan I, Yildirim E, Kala EY. In vitro wound healing activity of wheat-derived Nanovesicles. Appl Biochem Biotechnol. 2019; 188: 381-94. https://doi.org/10.1007/s12010-018-2913-1.

[118] Yang C, Zhang W, Bai M, Luo Q, Zheng Q, Xu Y, et al. Edible plant-derived extracellular vesicles serve as promising therapeutic systems. Nano TransMed. 2023; 2: 100004. https://doi.org/10.1016/j.ntm.2023.100004.

[119] Cho EG, Choi SY, Kim H, Choi EJ, Lee EJ, Park PJ, et al. Panax ginseng-derived extracellular vesicles facilitate anti-senescence effects in human skin cells: an eco-friendly and sustainable way to use ginseng substances. Cells. 2021; 10: 486. https://doi.org/10.3390/cells10030486.

[120] Kim MK, Choi YC, Cho SH, Choi JS, Cho YW. The antioxidant effect of small extracellular vesicles derived from Aloe vera peels for wound healing. Tissue Eng Regen Med. 2021; 18: 561-71. https://doi.org/10.1007/s13770-021-00367-8.

[121] Perut F, Roncuzzi L, Avnet S, Massa A, Zini N, Sabbadini S, et al. Strawberry-derived exosome-like nanoparticles prevent oxidative stress in human mesenchymal stromal cells. Biomol Ther. 2021; 11: 87. https://doi.org/10.3390/biom11010087.

[122] Ramirez O, Pomareda F, Olivares B, Huang YL, Zavala G, Carrasco-Rojas J, et al. Aloe vera peel-derived nanovesicles display anti-inflammatory properties and prevent myofibroblast differentiation. Phytomedicine. 2024; 122: 155108. https://doi.org/10.1016/j.phymed.2023.155108.

[123] Feng J, Xiu Q, Huang Y, Troyer Z, Li B, Zheng L. Plant-derived vesicle-like nanoparticles as promising biotherapeutic tools: present and future. Adv Mater. 2023; 35: e2207826.

[124] Lian MQ, Chng WH, Liang J, Yeo HQ, Lee CK, Belaid M, et al. Plant-derived extracellular vesicles: recent advancements and current challenges on their use for biomedical applications. J Extracell Vesicles. 2022; 11:e12283. https://doi.org/10.1002/jev2.12283.

[125] Cong M, Tan S, Li S, Gao L, Huang L, Zhang HG, et al. Technology insight: plant-derived vesicles-how far from the clinical biotherapeutics and therapeutic drug carriers? Adv Drug Deliv Rev. 2022; 182: 114108. https://doi.org/10.1016/j.addr.2021.114108.

[126] Rahmati S, Karimi H, Alizadeh M, Khazaei AH, Paiva-Santos AC, Rezakhani L, et al. Prospects of plant-derived exosome-like nanocarriers in oncology and tissue engineering. Hum Cell. 2024; 37: 121-38. https://doi.org/10.1007/s13577-023-00994-4.

[127] Santos-Merino M, Gutierrez-Lanza R, Nogales J, Garcia JL, de la Cruz F. Synechococcus elongatus PCC 7942 as a platform for bioproduction of Omega-3 fatty acids. Life (Basel). 2022; 12: 810.

[128] Yin H, Chen CY, Liu YW, Tan YJ, Deng ZL, Yang F, et al. Synechococcus elongatus PCC7942 secretes extracellular vesicles to accelerate cutaneous wound healing by promoting angiogenesis. Theranostics. 2019; 9: 2678-93. https://doi.org/10.7150/thno.31884.

[129] Fan Z, Jiang C, Wang Y, Wang K, Marsh J, Zhang D, et al. Engineered extracellular vesicles as intelligent nanosystems for next-generation nanomedicine. Nanoscale Horiz. 2022; 7: 682-714. https://doi.org/10.1039/D2NH00070A.

[130] Wu P, Zhang B, Ocansey DKW, Xu W, Qian H. Extracellular vesicles: a bright star of nanomedicine. Biomaterials. 2021; 269: 120467. https://doi.org/10.1016/j.biomaterials.2020.120467.

[131] Liu C, He D, Cen H, Chen H, Li L, Nie G, et al. Nucleic acid functionalized extracellular vesicles as promising therapeutic systems for nanomedicine. Extracellular Vesicles and Circulating Nucleic Acids. 3: 14-30.

[132] Shi X, Fu N, Zhang H, Brown-Borg HM, Wang S, Zhao RC. Bioengineering strategies for augmenting wound-healing efficacy of mesenchymal stem cell-derived extracellular vesicles. Sci Bull (Beijing). 2024; S2095-9273:00767-9. https://doi.org/10.1016/j.scib.2024.10.024.

[133] Man K, Eisenstein NM, Hoey DA, Cox SC. Bioengineering extracellular vesicles: smart nanomaterials for bone regeneration. J Nanobiotechnology. 2023; 21: 137. https://doi.org/10.1186/s12951-023-01895-2.

[134] Huang CC, Kang M, Lu Y, Shirazi S, Diaz JI, Cooper LF, et al. Functionally engineered extracellular vesicles improve bone regeneration. Acta Biomater. 2020; 109: 182-94. https://doi.org/10.1016/j.actbio.2020.04.017.

[135] Jiang L, Zhang Y, Liu T, Wang X, Wang H, Song H, et al. Exosomes derived from TSG-6 modified mesenchymal stromal cells attenuate scar formation during wound healing. Biochimie. 2020; 177: 40-9. https://doi.org/10.1016/j.biochi.2020.08.003.

[136] Li X, Xie X, Lian W, Shi R, Han S, Zhang H, et al. Exosomes from adipose-derived stem cells overexpressing Nrf2 accelerate cutaneous wound healing by promoting vascularization in a diabetic foot ulcer rat model. Exp Mol Med. 2018; 50: 1-14. https://doi.org/10.1038/s12276-018-0058-5.

[137] Born LJ, Chang KH, Shoureshi P, Lay F, Bengali S, Hsu ATW, et al. HOTAIR-loaded mesenchymal stem/stromal cell extracellular vesicles enhance angiogenesis and wound healing. Adv Healthc Mater. 2022; 11: e2002070. https://doi.org/10.1002/adhm.202002070.

[138] Gondaliya P, Sayyed AA, Bhat P, Mali M, Arya N, Khairnar A, et al. Mesenchymal stem cell-derived exosomes loaded with miR-155 inhibitor ameliorate diabetic wound healing. Mol Pharm. 2022; 19: 1294-308. https://doi.org/10.1021/acs.molpharmaceut.1c00669.

[139] Lv Q, Deng J, Chen Y, Wang Y, Liu B, Liu J. Engineered human adipose stem-cell-derived exosomes loaded with miR-21-5p to promote diabetic cutaneous wound healing. Mol Pharm. 2020; 17: 1723-33. https://doi.org/10.1021/acs.molpharmaceut.0c00177.

[140] Zhou X, Ye C, Jiang L, Zhu X, Zhou F, Xia M, et al. The bone mesenchymal stem cell-derived exosomal miR-146a-5p promotes diabetic wound healing in mice via macrophage M1/M2 polarization. Mol Cell Endocrinol. 2024; 579: 112089. https://doi.org/10.1016/j.mce.2023.112089.

[141] Syn NL, Wang L, Chow EK, Lim CT, Goh BC. Exosomes in cancer Nanomedicine and immunotherapy: prospects and challenges. Trends Biotechnol. 2017; 35: 665-76. https://doi.org/10.1016/j.tibtech.2017.03.004.

[142] Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, et al. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Control Release. 2015;207:18-30. https://doi.org/10.1016/j.jconrel.2015.03.033.

[143] Sato YT, Umezaki K, Sawada S, Mukai SA, Sasaki Y, Harada N, et al. Engineering hybrid exosomes by membrane fusion with liposomes. Sci Rep. 2016; 6: 21933. https://doi.org/10.1038/srep21933.

[144] Zhang Y, Wang S, Yang Y, Zhao S, You J, Wang J, et al. Scarless wound healing programmed by core-shell microneedles. Nat Commun. 2023; 14: 3431. https://doi.org/10.1038/s41467-023-39129-6.

[145] Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972; 26: 239-57. https://doi.org/10.1038/bjc.1972.33.

[146] Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to Chemotoxicity and aging. Cell. 2017; 169: 132-147.e16. https://doi.org/10.1016/j.cell.2017.02.031.

[147] Tixeira R, Caruso S, Paone S, Baxter AA, Atkin-Smith GK, Hulett MD, et al. Defining the morphologic features and products of cell disassembly during apoptosis. Apoptosis. 2017; 22: 475-7. https://doi.org/10.1007/s10495-017-1345-7.

[148] Kakarla R, Hur J, Kim YJ, Kim J, Chwae YJ. Apoptotic cell-derived exosomes: messages from dying cells. Exp Mol Med. 2020; 52: 1-6. https://doi.org/10.1038/s12276-019-0362-8.

[149] Song N, Scholtemeijer M, Shah K. Mesenchymal stem cell immunomodulation: mechanisms and therapeutic potential. Trends Pharmacol Sci. 2020; 41: 653-64. https://doi.org/10.1016/j.tips.2020.06.009.

[150] Zhu Y, Yang K, Cheng Y, Liu Y, Gu R, Liu X, et al. Apoptotic vesicles regulate bone metabolism via the miR1324/SNX14/SMAD1/5 Signaling Axis. Small. 2023; 19: e2205813. https://doi.org/10.1002/smll.202205813.

[151] Li Z, Wu M, Liu S, Liu X, Huan Y, Ye Q, et al. Apoptotic vesicles activate autophagy in recipient cells to induce angiogenesis and dental pulp regeneration. Mol Ther. 2022; 30: 3193-208. https://doi.org/10.1016/j.ymthe.2022.05.006.

[152] Brock CK, Wallin ST, Ruiz OE, Samms KM, Mandal A, Sumner EA, et al. Stem cell proliferation is induced by apoptotic bodies from dying cells during epithelial tissue maintenance. Nat Commun. 2019; 10: 1044. https://doi.org/10.1038/s41467-019-09010-6.

[153] Xin L, Wei C, Tong X, Dai Y, Huang D, Chen J, et al. In situ delivery of apoptotic bodies derived from mesenchymal stem cells via a hyaluronic acid hydrogel: a therapy for intrauterine adhesions. Bioact Mater. 2022; 12: 107-19. https://doi.org/10.1016/j.bioactmat.2021.10.025.

[154] Ma L, Chen C, Liu D, Huang Z, Li J, Liu H, et al. Apoptotic extracellular vesicles are metabolized regulators nurturing the skin and hair. Bioact Mater. 2023; 19: 626-41. https://doi.org/10.1016/j.bioactmat.2022.04.022.

[155] Liu J, Qiu X, Lv Y, Zheng C, Dong Y, Dou G, et al. Apoptotic bodies derived from mesenchymal stem cells promote cutaneous wound healing via regulating the functions of macrophages. Stem Cell Res Ther. 2020; 11: 507. https://doi.org/10.1186/s13287-020-02014-w.

[156] Qu Y, He Y, Meng B, Zhang X, Ding J, Kou X, et al. Apoptotic vesicles inherit SOX2 from pluripotent stem cells to accelerate wound healing by energizing mesenchymal stem cells. Acta Biomater. 2022; 149: 258-72. https://doi.org/10.1016/j.actbio.2022.07.009.

[157] Mao J, Qian S, Zhao Q, Zhao B, Lu B, Zhang L, et al. Balancing macrophage polarization via stem cell-derived apoptotic bodies for diabetic wound healing. Med. 2024; 5: 148-168.e8. https://doi.org/10.1016/j.medj.2024.01.006.

[158] Al-Masawa ME, Alshawsh MA, Ng CY, Ng AMH, Foo JB, Vijakumaran U, et al. Efficacy and safety of small extracellular vesicle interventions in wound healing and skin regeneration: a systematic review and meta-analysis of animal studies. Theranostics. 2022; 12: 6455-508. https://doi.org/10.7150/thno.73436.

[159] Dong J, Wu Y, Zhang Y, Yu M, Tian W. Comparison of the therapeutic effect of allogeneic and xenogeneic small extracellular vesicles in soft tissue repair. Int J Nanomedicine. 2020; 15: 6975-91. https://doi.org/10.2147/IJN.S269069.

[160] Lu M, Peng L, Ming X, Wang X, Cui A, Li Y, et al. Enhanced wound healing promotion by immune response-free monkey autologous iPSCs and exosomes vs. their allogeneic counterparts. EBioMedicine. 2019; 42: 443-57. https://doi.org/10.1016/j.ebiom.2019.03.011.

[161] Giebel B, Kordelas L, Borger V. Clinical potential of mesenchymal stem/stromal cell-derived extracellular vesicles. Stem Cell Investig. 2017; 4: 84. https://doi.org/10.21037/sci.2017.09.06.

[162] de Castilla PEM, Tong L, Huang C, Sofias AM, Pastorin G, Chen X, et al. Extracellular vesicles as a drug delivery system: a systematic review of preclinical studies.Adv Drug Deliv Rev. 2021; 175: 113801. https://doi.org/10.1016/j.addr.2021.05.011.

[163] Haraszti RA, Miller R, Stoppato M, Sere YY, Coles A, Didiot MC, et al. Exosomes produced from 3D cultures of MSCs by tangential flow filtration show higher yield and improved activity. Mol Ther. 2018; 26: 2838-47. https://doi.org/10.1016/j.ymthe.2018.09.015.

[164] Rocha S, Carvalho J, Oliveira P, Voglstaetter M, Schvartz D, Thomsen AR, et al. 3D cellular architecture affects MicroRNA and protein cargo of extracellular vesicles. Adv Sci (Weinh). 2019; 6: 1800948. https://doi.org/10.1002/advs.201800948.

[165] Lin R, Zhang T, Gao J. Apoptotic vesicles of MSCs: the natural therapeutic agents and bio-vehicles for targeting drug delivery. Small. 2023; 19: e2301671. https://doi.org/10.1002/smll.202301671.

[166] Charoenviriyakul C, Takahashi Y, Morishita M, Matsumoto A, Nishikawa M, Takakura Y. Cell type-specific and common characteristics of exosomes derived from mouse cell lines: yield, physicochemical properties, and pharmacokinetics. Eur J Pharm Sci. 2017; 96: 316-22. https://doi.org/10.1016/j.ejps.2016.10.009.

[167] Venugopal C, Shamir C, Senthilkumar S, Babu JV, Sonu PK, Nishtha KJ, et al. Dosage and passage dependent neuroprotective effects of exosomes derived from rat bone marrow mesenchymal stem cells: an in vitro analysis. Curr Gene Ther. 2017; 17: 379-90. https://doi.org/10.2174/1566523218666180125091952.