Therapeutic Potential of M2 Macrophage-Derived Exosomes in Regenerative Medicine

Document Type : Analytic Review

Author
1. Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Abstract
M2 macrophages and their exosome-derived products have therapeutic potential in regenerative medicine. M2 macrophages, characterized by their anti-inflammatory and tissue-repair functions, play pivotal roles in immune modulation, wound healing, and disease resolution. M2 macrophage-derived exosomes can modulate inflammatory responses, promote angiogenesis, and stimulate stem cell activity.

The review systematically examines their roles in diverse preclinical models, including diabetic fractures, periodontitis, neurodegenerative diseases, myocardial infarction, and chronic wounds. It addresses progress in bioengineering, such as combining M2-derived exosomes with biomaterials and scaffolds to improve targeted delivery and regenerative results. Although they show great potential, obstacles like exosome diversity, restricted scalability, and the need for standardized isolation techniques are recognized as hindrances to clinical application.
This review distinguishes M2 macrophage-derived exosomes as a promising acellular tool for personalized therapeutic applications and tissue repair by synthesizing existing literature and identifying promising directions for future research. It emphasizes the need for ongoing research to overcome technical and regulatory barriers to their successful translation to the clinical setting

Keywords

Subjects


1. Chen S, Saeed AFUH, Liu Q, Jiang Q, Xu H, Xiao GG, et al. Macrophages in immunoregulation and therapeutics. Signal Transduct Target Ther [Internet]. 2023;8(1):207. Available from: https://doi.org/10.1038/s41392-023-01452-1
2. Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014;5:491.
3. Arora S, Dev K, Agarwal B, Das P, Syed MA. Macrophages: Their role, activation and polarization in pulmonary diseases. Immunobiology. 2018;223(4–5):383–96.
4. Laskin DL, Sunil VR, Gardner CR, Laskin JD. Macrophages and tissue injury: agents of defense or destruction? Annu Rev Pharmacol Toxicol. 2011;51:267–88.
5. Zhang Z, Tang J, Cui X, Qin B, Zhang J, Zhang L, et al. New Insights and Novel Therapeutic Potentials for Macrophages in Myocardial Infarction. Inflammation. 2021 Oct;44(5):1696–712.
6. Vučemilović A. Exosomes: intriguing mediators of intercellular communication in the organism’s response to noxious agents. Arh Hig Rada Toksikol. 2024 Dec;75(4):228–39.
7. Wang Y, Lin Q, Zhang H, Wang S, Cui J, Hu Y, et al. M2 macrophage-derived exosomes promote diabetic fracture healing by acting as an immunomodulator. Bioact Mater [Internet]. 2023;28:273–83. Available from: https://www.sciencedirect.com/science/article/pii/S2452199X23001706
8. Wang C, Xu M, Fan Q, Li C, Zhou X. Therapeutic potential of exosome-based personalized delivery platform in chronic inflammatory diseases. Asian J Pharm Sci. 2023 Jan;18(1):100772.
9. Chen J, Hu S, Liu J, Jiang H, Wang S, Yang Z. Exosomes: a double-edged sword in cancer immunotherapy. MedComm [Internet]. 2025;6(3):e70095. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/mco2.70095
10. Wu Y, Hirschi KK. Tissue-Resident Macrophage Development and Function. Front cell Dev Biol. 2020;8:617879.
11. Yahara Y, Ma X, Gracia L, Alman BA. Monocyte/Macrophage Lineage Cells From Fetal Erythromyeloid Progenitors Orchestrate Bone Remodeling and Repair. Front cell Dev Biol. 2021;9:622035.
12. Orkin SH, Zon LI. Hematopoiesis: an evolving paradigm for stem cell biology. Cell. 2008 Feb;132(4):631–44.
13. Epelman S, Lavine KJ, Randolph GJ. Origin and functions of tissue macrophages. Immunity. 2014 Jul;41(1):21–35.
14. Sreejit G, Fleetwood AJ, Murphy AJ, Nagareddy PR. Origins and diversity of macrophages in health and disease. Clin Transl Immunol. 2020;9(12):e1222.
15. Guan F, Wang R, Yi Z, Luo P, Liu W, Xie Y, et al. Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets. Signal Transduct Target Ther. 2025 Mar;10(1):93.
16. Röszer T. Understanding the Biology of Self-Renewing Macrophages. Cells. 2018 Aug;7(8).
17. Li J, Xiao C, Li C, He J. Tissue-resident immune cells: from defining characteristics to roles in diseases. Signal Transduct Target Ther [Internet]. 2025;10(1):12. Available from: https://doi.org/10.1038/s41392-024-02050-5
18. Bennett CL, Perona-Wright G. Metabolic adaption of mucosal macrophages: Is metabolism a driver of persistence across tissues? Mucosal Immunol. 2023 Oct;16(5):753–63.
19. Cao M, Wang Z, Lan W, Xiang B, Liao W, Zhou J, et al. The roles of tissue resident macrophages in health and cancer. Exp Hematol Oncol. 2024 Jan;13(1):3.
20. Mettelman RC, Allen EK, Thomas PG. Mucosal immune responses to infection and vaccination in the respiratory tract. Immunity. 2022 May;55(5):749–80.
21. Mosser DM, Hamidzadeh K, Goncalves R. Macrophages and the maintenance of homeostasis. Cell Mol Immunol [Internet]. 2021;18(3):579–87. Available from: https://doi.org/10.1038/s41423-020-00541-3
22. Hirayama D, Iida T, Nakase H. The Phagocytic Function of Macrophage-Enforcing Innate Immunity and Tissue Homeostasis. Int J Mol Sci. 2017 Dec;19(1).
23. Li D, Wu M. Pattern recognition receptors in health and diseases. Signal Transduct Target Ther [Internet]. 2021;6(1):291. Available from: https://doi.org/10.1038/s41392-021-00687-0
24. Kourtzelis I, Hajishengallis G, Chavakis T. Phagocytosis of Apoptotic Cells in Resolution of Inflammation. Front Immunol. 2020;11:553.
25. Wynn TA, Vannella KM. Macrophages in Tissue Repair, Regeneration, and Fibrosis. Immunity. 2016 Mar;44(3):450–62.
26. Krzyszczyk P, Schloss R, Palmer A, Berthiaume F. The Role of Macrophages in Acute and Chronic Wound Healing and Interventions to Promote Pro-wound Healing Phenotypes. Front Physiol. 2018;9:419.
27. Strizova Z, Benesova I, Bartolini R, Novysedlak R, Cecrdlova E, Foley LK, et al. M1/M2 macrophages and their overlaps - myth or reality? Clin Sci (Lond). 2023 Aug;137(15):1067–93.
28. Viola A, Munari F, Sánchez-Rodríguez R, Scolaro T, Castegna A. The Metabolic Signature of Macrophage Responses. Front Immunol [Internet]. 2019;Volume 10. Available from: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01462
29. Rőszer T. Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms. Mediators Inflamm. 2015;2015:816460.
30. Ross EA, Devitt A, Johnson JR. Macrophages: The Good, the Bad, and the Gluttony. Front Immunol [Internet]. 2021;12. Available from: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.708186
31. Moestrup SK, Møller HJ. CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. Ann Med. 2004;36(5):347–54.
32. Yu Y, Yue Z, Xu M, Zhang M, Shen X, Ma Z, et al. Macrophages play a key role in tissue repair and regeneration. PeerJ. 2022;10:e14053.
33. Wang LX, Zhang SX, Wu HJ, Rong XL, Guo J. M2b macrophage polarization and its roles in diseases. J Leukoc Biol. 2019 Aug;106(2):345–58.
34. Zizzo G, Hilliard BA, Monestier M, Cohen PL. Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction. J Immunol. 2012 Oct;189(7):3508–20.
35. Hao NB, Lü MH, Fan YH, Cao YL, Zhang ZR, Yang SM. Macrophages in tumor microenvironments and the progression of tumors. Clin Dev Immunol. 2012;2012:948098.
36. Xu F, Zhang Q, Liu Y, Tang R, Li H, Yang H, et al. The Role of Exosomes Derived from Various Sources in Facilitating the Healing of Chronic Refractory Wounds. Pharmacol Res [Internet]. 2025;107753. Available from: https://www.sciencedirect.com/science/article/pii/S1043661825001781
37. Song Y, Hu J, Ma C, Liu H, Li Z, Yang Y. Macrophage-Derived Exosomes as Advanced Therapeutics for Inflammation: Current Progress and Future Perspectives. Int J Nanomedicine. 2024;19:1597–627.
38. Zhang Y, Lan M, Chen Y. Minimal Information for Studies of Extracellular Vesicles (MISEV): Ten-Year Evolution (2014-2023). Pharmaceutics. 2024 Oct;16(11).
39. Gurung S, Perocheau D, Touramanidou L, Baruteau J. The exosome journey: from biogenesis to uptake and intracellular signalling. Cell Commun Signal [Internet]. 2021;19(1):47. Available from: https://doi.org/10.1186/s12964-021-00730-1
40. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020 Feb;367(6478).
41. Andreu Z, Yáñez-Mó M. Tetraspanins in extracellular vesicle formation and function. Front Immunol. 2014;5:442.
42. Sidhom K, Obi PO, Saleem A. A Review of Exosomal Isolation Methods: Is Size Exclusion Chromatography the Best Option? Int J Mol Sci. 2020 Sep;21(18).
43. Onódi Z, Pelyhe C, Terézia Nagy C, Brenner GB, Almási L, Kittel Á, et al. Isolation of High-Purity Extracellular Vesicles by the Combination of Iodixanol Density Gradient Ultracentrifugation and Bind-Elute Chromatography From Blood Plasma. Front Physiol. 2018;9:1479.
44. Mukerjee N, Bhattacharya A, Maitra S, Kaur M, Ganesan S, Mishra S, et al. Exosome isolation and characterization for advanced diagnostic and therapeutic applications. Mater Today Bio [Internet]. 2025;31:101613. Available from: https://www.sciencedirect.com/science/article/pii/S2590006425001711
45. Dilsiz N. A comprehensive review on recent advances in exosome isolation and characterization: Toward clinical applications. Transl Oncol [Internet]. 2024;50:102121. Available from: https://www.sciencedirect.com/science/article/pii/S1936523324002481
46. Ansari FJ, Tafti HA, Amanzadeh A, Rabbani S, Shokrgozar MA, Heidari R, et al. Comparison of the efficiency of ultrafiltration, precipitation, and ultracentrifugation methods for exosome isolation. Biochem Biophys Reports [Internet]. 2024;38:101668. Available from: https://www.sciencedirect.com/science/article/pii/S2405580824000323
47. Aheget H, Mazini L, Martin F, Belqat B, Marchal JA, Benabdellah K. Exosomes: Their Role in Pathogenesis, Diagnosis and Treatment of Diseases. Cancers (Basel). 2020 Dec;13(1).
48. Liu YJ, Wang C. A review of the regulatory mechanisms of extracellular vesicles-mediated intercellular communication. Cell Commun Signal. 2023 Apr;21(1):77.
49. Tai YL, Chen KC, Hsieh JT, Shen TL. Exosomes in cancer development and clinical applications. Cancer Sci. 2018 Aug;109(8):2364–74.
50. Li J, Wang J, Chen Z. Emerging role of exosomes in cancer therapy: progress and challenges. Mol Cancer [Internet]. 2025;24(1):13. Available from: https://doi.org/10.1186/s12943-024-02215-4
51. Butreddy A, Kommineni N, Dudhipala N. Exosomes as Naturally Occurring Vehicles for Delivery of Biopharmaceuticals: Insights from Drug Delivery to Clinical Perspectives. Nanomater (Basel, Switzerland). 2021 Jun;11(6).
52. Li T, Li X, Han G, Liang M, Yang Z, Zhang C, et al. The Therapeutic Potential and Clinical Significance of Exosomes as Carriers of Drug Delivery System. Pharmaceutics. 2022 Dec;15(1).
53. Abdelsalam M, Ahmed M, Osaid Z, Hamoudi R, Harati R. Insights into Exosome Transport through the Blood-Brain Barrier and the Potential Therapeutical Applications in Brain Diseases. Pharmaceuticals (Basel). 2023 Apr;16(4).
54. Basyoni AE, Atta A, Salem MM, Mohamed TM. Harnessing exosomes for targeted drug delivery systems to combat brain cancer. Cancer Cell Int [Internet]. 2025;25(1):150. Available from: https://doi.org/10.1186/s12935-025-03731-z
55. Ha D, Yang N, Nadithe V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharm Sin B. 2016 Jul;6(4):287–96.
56. Zeng H, Guo S, Ren X, Wu Z, Liu S, Yao X. Current Strategies for Exosome Cargo Loading and Targeting Delivery. Cells. 2023 May;12(10).
57. Zhang Y, Bi J, Huang J, Tang Y, Du S, Li P. Exosome: A Review of Its Classification, Isolation Techniques, Storage, Diagnostic and Targeted Therapy Applications. Int J Nanomedicine. 2020;15:6917–34.
58. Zhang W, Zhou R, Liu X, You L, Chen C, Ye X, et al. Key role of exosomes derived from M2 macrophages in maintaining cancer cell stemness (Review). Int J Oncol. 2023 Nov;63(5).
59. Shan X, Zhang C, Mai C, Hu X, Cheng N, Chen W, et al. The Biogenesis, Biological Functions, and Applications of Macrophage-Derived Exosomes. Front Mol Biosci. 2021;8:715461.
60. Liu G, Cao R, Liu Q, Li H, Yan P, Wang K, et al. M2 macrophages-derived exosomes for osteonecrosis of femoral head treatment: modulating neutrophil extracellular traps formation and endothelial phenotype transition. Bone Res [Internet]. 2025;13(1):42. Available from: https://doi.org/10.1038/s41413-025-00412-5
61. Zhou Y, Hu G. M2 macrophages-derived exosomes regulate osteoclast differentiation by the CSF2/TNF-α axis. BMC Oral Health. 2024 Jan;24(1):107.
62. Gao J, Wu Z. M2 macrophage-derived exosomes enable osteogenic differentiation and inhibit inflammation in human periodontal ligament stem cells through promotion of CXCL12 expression. BMC Oral Health. 2024 Sep;24(1):1070.
63. Chen X, Wan Z, Yang L, Song S, Fu Z, Tang K, et al. Exosomes derived from reparative M2-like macrophages prevent bone loss in murine periodontitis models via IL-10 mRNA. J Nanobiotechnology. 2022 Mar;20(1):110.
64. Liao XM, Guan Z, Yang ZJ, Ma LY, Dai YJ, Liang C, et al. Comprehensive analysis of M2 macrophage-derived exosomes facilitating osteogenic differentiation of human periodontal ligament stem cells. BMC Oral Health. 2022 Dec;22(1):647.
65. Huang X, Deng Y, Xiao J, Wang H, Yang Q, Cao Z. Genetically engineered M2-like macrophage-derived exosomes for P. gingivalis-suppressed cementum regeneration: From mechanism to therapy. Bioact Mater. 2024 Feb;32:473–87.
66. Huang X, Wang X, Ma L, Wang H, Peng Y, Liu H, et al. M2 macrophages with inflammation tropism facilitate cementoblast mineralization. J Periodontol [Internet]. 2023;94(2):290–300. Available from: https://aap.onlinelibrary.wiley.com/doi/abs/10.1002/JPER.22-0048
67. Dutta SD, An JM, Hexiu J, Randhawa A, Ganguly K, Patil T V, et al. 3D bioprinting of engineered exosomes secreted from M2-polarized macrophages through immunomodulatory biomaterial promotes in vivo wound healing and angiogenesis. Bioact Mater. 2025 Mar;45:345–62.
68. Kim H, Wang SY, Kwak G, Yang Y, Kwon IC, Kim SH. Exosome-Guided Phenotypic Switch of M1 to M2 Macrophages for Cutaneous Wound Healing. Adv Sci (Weinheim, Baden-Wurttemberg, Ger. 2019 Oct;6(20):1900513.
69. Lyu L, Cai Y, Zhang G, Jing Z, Liang J, Zhang R, et al. Exosomes derived from M2 macrophages induce angiogenesis to promote wound healing. Front Mol Biosci. 2022;9:1008802.
70. Luo G, Zhou Z, Cao Z, Huang C, Li C, Li X, et al. M2 macrophage-derived exosomes induce angiogenesis and increase skin flap survival through HIF1AN/HIF-1α/VEGFA control. Arch Biochem Biophys [Internet]. 2024;751:109822. Available from: https://www.sciencedirect.com/science/article/pii/S0003986123003211
71. Xie K, Mo Y, Yue E, Shi N, Liu K. Exosomes derived from M2-type microglia ameliorate oxygen-glucose deprivation/reoxygenation-induced HT22 cell injury by regulating miR-124-3p/NCOA4-mediated ferroptosis. Heliyon. 2023 Jul;9(7):e17592.
72. Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci Off J Soc Neurosci. 2009 Oct;29(43):13435–44.
73. Fu GQ, Wang YY, Xu YM, Bian MM, Zhang L, Yan HZ, et al. Exosomes derived from vMIP-II-Lamp2b gene-modified M2 cells provide neuroprotection by targeting the injured spinal cord, inhibiting chemokine signals and modulating microglia/macrophage polarization in mice. Exp Neurol. 2024 Jul;377:114784.
74. Yuan D, Zhao Y, Banks WA, Bullock KM, Haney M, Batrakova E, et al. Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain. Biomaterials. 2017 Oct;142:1–12.
75. Cheng X, Zhou H, Zhou Y, Song C. M2 Macrophage-Derived Exosomes Inhibit Apoptosis of HUVEC Cell through Regulating miR-221-3p Expression. Biomed Res Int. 2022;2022:1609244.
76. Wang S, Wang X, Lv Y, Zhang Z, He T, Hao X, et al. M2 Macrophage-Derived Exosomes Inhibit Atherosclerosis Progression by Regulating the Proliferation, Migration, and Phenotypic Transformation of Smooth Muscle Cells. Front Biosci (Landmark Ed. 2024 Aug;29(8):288.
77. Wang X, Xu C, Bian C, Ge P, Lei J, Wang J, et al. M2 microglia-derived exosomes promote vascular remodeling in diabetic retinopathy. J Nanobiotechnology [Internet]. 2024;22(1):56. Available from: https://doi.org/10.1186/s12951-024-02330-w
78. Long R, Gao L, Li Y, Li G, Qin P, Wei Z, et al. M2 macrophage-derived exosomes carry miR-1271-5p to alleviate cardiac injury in acute myocardial infarction through down-regulating SOX6. Mol Immunol. 2021 Aug;136:26–35.
79. Li Z, Cao Z, Li N, Wang L, Fu C, Huo R, et al. M2 Macrophage-Derived Exosomal lncRNA MIR4435-2HG Promotes Progression of Infantile Hemangiomas by Targeting HNRNPA1. Int J Nanomedicine. 2023;18:5943–60.
80. Da-Wa ZX, Jun M, Chao-Zheng L, Sen-Lin Y, Chuan L, De-Chun L, et al. Exosomes Derived from M2 Macrophages Exert a Therapeutic Effect via Inhibition of the PI3K/AKT/mTOR Pathway in Rats with Knee Osteoarthritic. Biomed Res Int. 2021;2021:7218067.
81. Yang R, Liao Y, Wang L, He P, Hu Y, Yuan D, et al. Exosomes Derived From M2b Macrophages Attenuate DSS-Induced Colitis. Front Immunol. 2019;10:2346.
82. Zheng N, Wang T, Luo Q, Liu Y, Yang J, Zhou Y, et al. M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance. Oncoimmunology. 2023;12(1):2210959.
83. Hu W, Wang W, Chen Z, Chen Y, Wang Z. Engineered exosomes and composite biomaterials for tissue regeneration. Theranostics. 2024;14(5):2099–126.
84. Sun X, Mao Y, Liu B, Gu K, Liu H, Du W, et al. Mesenchymal Stem Cell-Derived Exosomes Enhance 3D-Printed Scaffold Functions and Promote Alveolar Bone Defect Repair by Enhancing Angiogenesis. J Pers Med. 2023 Jan;13(2).
85. Meng H, Su J, Shen Q, Hu W, Li P, Guo K, et al. A Smart MMP-9-responsive Hydrogel Releasing M2 Macrophage-derived Exosomes for Diabetic Wound Healing. Adv Healthc Mater. 2025 Apr;14(10):e2404966.
86. Wang T, Zhou Y, Zhang W, Xue Y, Xiao Z, Zhou Y, et al. Exosomes and exosome composite scaffolds in periodontal tissue engineering. Front Bioeng Biotechnol [Internet]. 2024;Volume 11. Available from: https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2023.1287714
87. Wang CK, Tsai TH, Lee CH. Regulation of exosomes as biologic medicines: Regulatory challenges faced in exosome development and manufacturing processes. Clin Transl Sci. 2024 Aug;17(8):e13904.
88. Liu L, Jiang D, Bai S, Zhang X, Kang Y. Research progress of exosomes in drug resistance of breast cancer. Front Bioeng Biotechnol. 2023;11:1214648.
89. Liu L, Zhang S, Ren Y, Wang R, Zhang Y, Weng S, et al. Macrophage-derived exosomes in cancer: a double-edged sword with therapeutic potential. J Nanobiotechnology. 2025 Apr;23(1):319.