Application and advances of exosome-hydrogel system in wound healing_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

QIU Yan ¹ ,  TAN Qian ^1,2

1. Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing Jiangsu, 210008, P. R. China;
2. Department of Burns & Plastic Surgery, Nanjing Drum Tower Hospital, Nanjing University, Nanjing Jiangsu, 210008, P. R. China;

Corresponding author：

TAN Qian, Email: smmutanqian@sina.com

Keywords：

Wound healing; exosome; hydrogel; biomaterial; tissue repair and regeneration

DOI：

10.7507/1002-1892.202506093

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To review the recent advances in the application of exosome-hydrogel system for wound healing. Methods A wide range of recent domestic and international studies were reviewed to systematically outline the roles and mechanisms of exosomes, hydrogels, and their composite system in promoting wound repair. Results Wound healing is a complex and finely regulated process. Traditional therapies lack targeted regulation of key mechanisms such as inflammation control, angiogenesis, collagen remodeling, and re-epithelialization. The exosome-hydrogel system enhances wound repair through targeted modulation of these mechanisms and provides effective protection against bacterial infection, hypoxia, excessive oxidative stress, and hyperglycemic microenvironments. Conclusion The exosome–hydrogel system represents an emerging approach for chronic wound repair and skin regeneration, potentially overcoming the inherent limitations of traditional therapies. Nevertheless, the lack of standardized preparation methods and dosing protocols calls for further optimization.

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1. Rodrigues M, Kosaric N, Bonham CA, et al. Wound healing: A cellular perspective. Physiol Rev, 2019, 99(1): 665-706.
2. Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med, 2014, 6(265): 265sr6. doi: 10.1126/scitranslmed.3009337.
3. Oliveira A, Simões S, Ascenso A, et al. Therapeutic advances in wound healing. J Dermatolog Treat, 2022, 33(1): 2-22.
4. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science, 2020, 367(6478): eaau6977. doi: 10.1126/science.aau6977.
5. Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells, 2017, 35(4): 851-858.
6. Cao H, Duan L, Zhang Y, et al. Current hydrogel advances in physicochemical and biological response-driven biomedical application diversity. Signal Transduct Target Ther, 2021, 6(1): 426. doi: 10.1038/s41392-021-00830-x.
7. Fan MH, Pi JK, Zou CY, et al. Hydrogel-exosome system in tissue engineering: A promising therapeutic strategy. Bioact Mater, 2024, 38: 1-30.
8. Velnar T, Bailey T, Smrkolj V. The wound healing process: an overview of the cellular and molecular mechanisms. J Int Med Res, 2009, 37(5): 1528-1542.
9. Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol, 2007, 127(3): 514-525.
10. Han C, Barakat M, DiPietro LA. Angiogenesis in wound repair: Too much of a good thing? Cold Spring Harb Perspect Biol, 2022, 14(10): a041225. doi: 10.1101/cshperspect.a041225.
11. Gurtner GC, Werner S, Barrandon Y, et al. Wound repair and regeneration. Nature, 2008, 453(7193): 314-321.
12. Cheng W, Yan-Hua R, Fang-Gang N, et al. The content and ratio of type Ⅰ and Ⅲ collagen in skin differ with age and injury. Afr J Biotechnol, 2011, 10(13): 2524-2529.
13. Schreml S, Szeimies RM, Prantl L, et al. Oxygen in acute and chronic wound healing. Br J Dermatol, 2010, 163(2): 257-268.
14. Mervis JS, Phillips TJ. Pressure ulcers: Pathophysiology, epidemiology, risk factors, and presentation. J Am Acad Dermatol, 2019, 81(4): 881-890.
15. Hedayati N, Carson JG, Chi YW, et al. Management of mixed arterial venous lower extremity ulceration: A review. Vasc Med, 2015, 20(5): 479-486.
16. Berlanga-Acosta J, Schultz GS, López-Mola E, et al. Glucose toxic effects on granulation tissue productive cells: the diabetics’ impaired healing. Biomed Res Int, 2013, 2013: 256043. doi: 10.1155/2013/256043.
17. Uberoi A, McCready-Vangi A, Grice EA. The wound microbiota: microbial mechanisms of impaired wound healing and infection. Nat Rev Microbiol, 2024, 22(8): 507-521.
18. Eriksson E, Liu PY, Schultz GS, et al. Chronic wounds: Treatment consensus. Wound Repair Regen, 2022, 30(2): 156-171.
19. Falanga V, Isseroff RR, Soulika AM, et al. Chronic wounds. Nat Rev Dis Primers, 2022, 8(1): 50. doi: 10.1038/s41572-022-00377-3.
20. Liang Y, He J, Guo B. Functional hydrogels as wound dressing to enhance wound healing. ACS Nano, 2021, 15(8): 12687-12722.
21. Jing YX, Huang T, Zhao B, et al. A ROS/glucose stimulated-responsive ADSCs-derived exosomes-release hydrogel system for diabetic wound healing. Chem Eng J, 2024, 487: 150561. doi: 10.1016/j.cej.2024.150561.
22. Cao Y, Chen B, Liu Q, et al. 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.
23. Lyu S, Liu Q, Yuen HY, et al. A differential-targeting core-shell microneedle patch with coordinated and prolonged release of mangiferin and MSC-derived exosomes for scarless skin regeneration. Mater Horiz, 2024, 11(11): 2667-2684.
24. Shen K, Zheng R, Yu BR, et al. Suppression the glucose-induced ferroptosis in endothelial cells by 4OI-loading exosomes hydrogel for the treatment of diabetic foot ulcer. Chem Eng J, 2024, 497: 154696. doi: 10.1016/j.cej.2024.154696.
25. Mogoşanu GD, Grumezescu AM. Natural and synthetic polymers for wounds and burns dressing. Int J Pharm, 2014, 463(2): 127-136.
26. Narayanaswamy R, Torchilin VP. Hydrogels and their applications in targeted drug delivery. Molecules, 2019, 24(3): 603. doi: 10.3390/molecules24030603.
27. Yuan J, Li M, He X, et al. A thermally stable bioactive chitosan scaffold with pH-responsive exosome adsorption and release function promotes wound healing. Int J Biol Macromol, 2025, 306(Pt 3): 141552. doi: 10.1016/j.ijbiomac.2025.141552.
28. Teng X, Liu T, Zhao G, et al. A novel exosome-based multifunctional nanocomposite platform driven by photothermal-controlled release system for repair of skin injury. J Control Release, 2024, 371: 258-272.
29. Wang X, Dong J, Kang J, et al. Self-adaptive release of stem cell-derived exosomes from a multifunctional hydrogel for accelerating MRSA-infected diabetic wound repair. J Am Chem Soc, 2025, 147(19): 16362-16378.
30. Meng H, Su J, Shen Q, et al. A smart MMP-9-responsive hydrogel releasing M2 macrophage-derived exosomes for diabetic wound healing. Adv Healthc Mater, 2025, 14(10): e2404966. doi: 10.1002/adhm.202404966.
31. Jin W, Li Y, Yu M, et al. Advances of exosomes in diabetic wound healing. Burns Trauma, 2025, 13: tkae078. doi: 10.1093/burnst/tkae078.
32. Liu C, Cheng C, Cheng K, et al. Precision exosome engineering for enhanced wound healing and scar revision. J Transl Med, 2025, 23(1): 578. doi: 10.1186/s12967-025-06578-0.
33. Mathieu M, Martin-Jaular L, Lavieu G, et al. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol, 2019, 21(1): 9-17.
34. Zhou Y, Zhang XL, Lu ST, et al. Human adipose-derived mesenchymal stem cells-derived exosomes encapsulated in pluronic F127 hydrogel promote wound healing and regeneration. Stem Cell Res Ther, 2022, 13(1): 407. doi: 10.1186/s13287-022-02980-3.
35. Shiekh PA, Singh A, Kumar A. Exosome laden oxygen releasing antioxidant and antibacterial cryogel wound dressing OxOBand alleviate diabetic and infectious wound healing. Biomaterials, 2020, 249: 120020. doi: 10.1016/j.biomaterials.2020.120020.
36. Yang Y, Zhang J, Wu S, et al. Exosome/antimicrobial peptide laden hydrogel wound dressings promote scarless wound healing through miR-21-5p-mediated multiple functions. Biomaterials, 2024, 308: 122558. doi: 10.1016/j.biomaterials.2024.122558.
37. Shi Y, Wang S, Wang K, et al. Relieving macrophage dysfunction by inhibiting SREBP2 activity: A hypoxic mesenchymal stem cells-derived exosomes loaded multifunctional hydrogel for accelerated diabetic wound healing. Small, 2024, 20(25): e2309276. doi: 10.1002/smll.202309276.
38. Zeng J, Sun Z, Zeng F, et al. M2 macrophage-derived exosome-encapsulated microneedles with mild photothermal therapy for accelerated diabetic wound healing. Mater Today Bio, 2023, 20: 100649. doi: 10.1016/j.mtbio.2023.100649.
39. Li W, Wu S, Ren L, et al. Development of an antiswelling hydrogel system incorporating M2-exosomes and photothermal effect for diabetic wound healing. ACS Nano, 2023, 17(21): 22106-22120.
40. Xu J, Lin S, Chen H, et al. Highly active frozen nanovesicles microneedles for senile wound healing via antibacteria, immunotherapy, and skin regeneration. Adv Healthc Mater, 2024, 13(12): e2304315. doi: 10.1002/adhm.202304315.
41. Yuan M, Liu K, Jiang T, et al. GelMA/PEGDA microneedles patch loaded with HUVECs-derived exosomes and Tazarotene promote diabetic wound healing. J Nanobiotechnology, 2022, 20(1): 147. doi: 10.1186/s12951-022-01354-4.
42. Wang S, Wu J, Ren K, et al. Platelet-rich plasma-derived exosome-encapsulated hydrogels accelerate diabetic wound healing by inhibiting fibroblast ferroptosis. ACS Appl Mater Interfaces, 2025, 17(19): 27923-27936.
43. Meng S, Wei Q, Chen S, et al. MiR-141-3p-functionalized exosomes loaded in dissolvable microneedle arrays for hypertrophic scar treatment. Small, 2024, 20(8): e2305374. doi: 10.1002/smll.202305374.
44. Fan MH, Zhang XZ, Jiang YL, et al. Exosomes from hypoxic urine-derived stem cells facilitate healing of diabetic wound by targeting SERPINE1 through miR-486-5p. Biomaterials, 2025, 314: 122893. doi: 10.1016/j.biomaterials.2024.122893.
45. Zhu D, Hu Y, Kong X, et al. Enhanced burn wound healing by controlled-release 3D ADMSC-derived exosome-loaded hyaluronan hydrogel. Regen Biomater, 2024, 11: rbae035. doi: 10.1093/rb/rbae035.
46. Peng H, Li HC, Zhang X, et al. 3D-exosomes laden multifunctional hydrogel enhances diabetic wound healing via accelerated angiogenesis. Chem Eng J, 2023, 475: 146238. doi: 10.1016/j.cej.2023.146238.
47. Yu H, Wang B, Li Z, et al. Corrigendum to ‘Tβ4-exosome-loaded hemostatic and antibacterial hydrogel to improve vascular regeneration and modulate macrophage polarization for diabetic wound treatment’ Mater. Today Bio, Volume 31, 2025, 101585. Mater Today Bio, 2025, 32: 101762. doi: 10.1016/j.mtbio.2025.101762.
48. Zhou Z, Bu Z, Wang S, et al. Extracellular matrix hydrogels with fibroblast growth factor 2 containing exosomes for reconstructing skin microstructures. J Nanobiotechnology, 2024, 22(1): 438. doi: 10.1186/s12951-024-02718-8.
49. Landén NX, Li D, Ståhle M. Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci, 2016, 73(20): 3861-3885.
50. Banerjee A, Singh P, Sheikh PA, et al. A multifunctional silk-hyaluronic acid self-healing hydrogel laden with alternatively activated macrophage-derived exosomes reshape microenvironment of diabetic wound and accelerate healing. Int J Biol Macromol, 2024, 270(Pt 2): 132384. doi: 10.1016/j.ijbiomac.2024.132384.
51. Shen Z, Wang L, Xie X, et al. Sprayable, antimicrobial and immunoregulation hydrogel loading exosomes based on oxidized sodium alginate for efficient wound healing at skin graft donor sites and health detection. Carbohydr Polym, 2025, 351: 123098. doi: 10.1016/j.carbpol.2024.123098.
52. Novak ML, Koh TJ. Phenotypic transitions of macrophages orchestrate tissue repair. Am J Pathol, 2013, 183(5): 1352-1363.
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