Spatiotemporally controlled restoration of GAS6 signaling via mRNA therapy promotes scarless healing in preclinical models

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Spatiotemporally controlled restoration of GAS6 signaling via mRNA therapy promotes scarless healing in preclinical models

References

  1. Gurtner, G. C., Werner, S., Barrandon, Y. & Longaker, M. T. Wound repair and regeneration. Nature 453, 314–321 (2008).

    Google Scholar 

  2. Falanga, V. et al. Chronic wounds. Nat. Rev. Dis. Primers 8, 50 (2022).

    Google Scholar 

  3. Jones, R. E., Foster, D. S. & Longaker, M. T. Management of chronic wounds-2018. JAMA 320, 1481–1482 (2018).

    Google Scholar 

  4. Martin, P., Pardo-Pastor, C., Jenkins, R. G. & Rosenblatt, J. Imperfect wound healing sets the stage for chronic diseases. Science 386, eadp2974 (2024).

    Google Scholar 

  5. Pena, O. A. & Martin, P. Cellular and molecular mechanisms of skin wound healing. Nat. Rev. Mol. Cell Biol. 25, 599–616 (2024).

    Google Scholar 

  6. Rodrigues, M., Kosaric, N., Bonham, C. A. & Gurtner, G. C. Wound healing: a cellular perspective. Physiol. Rev. 99, 665–706 (2019).

    Google Scholar 

  7. Uberoi, A., McCready-Vangi, A. & Grice, E. A. The wound microbiota: microbial mechanisms of impaired wound healing and infection. Nat. Rev. Microbiol. 22, 507–521 (2024).

    Google Scholar 

  8. Jeschke, M. G. et al. Scars. Nat. Rev. Dis. Primers 9, 64 (2023).

    Google Scholar 

  9. Bayat, A., McGrouther, D. A. & Ferguson, M. W. Skin scarring. BMJ 326, 88–92 (2003).

    Google Scholar 

  10. Finnerty, C. C. et al. Hypertrophic scarring: the greatest unmet challenge after burn injury. Lancet 388, 1427–1436 (2016).

    Google Scholar 

  11. Talbott, H. E., Mascharak, S., Griffin, M., Wan, D. C. & Longaker, M. T. Wound healing, fibroblast heterogeneity, and fibrosis. Cell Stem Cell 29, 1161–1180 (2022).

    Google Scholar 

  12. Correa-Gallegos, D. et al. CD201(+) fascia progenitors choreograph injury repair. Nature 623, 792–802 (2023).

    Google Scholar 

  13. Sinha, S. et al. Fibroblast inflammatory priming determines regenerative versus fibrotic skin repair in reindeer. Cell 185, 4717–4736.e4725 (2022).

    Google Scholar 

  14. Davidson, S. et al. Fibroblasts as immune regulators in infection, inflammation and cancer. Nat. Rev. Immunol. 21, 704–717 (2021).

    Google Scholar 

  15. Shook, B., Xiao, E., Kumamoto, Y., Iwasaki, A. & Horsley, V. CD301b+ macrophages are essential for effective skin wound healing. J. Investig. Dermatol. 136, 1885–1891 (2016).

    Google Scholar 

  16. Eming, S. A., Murray, P. J. & Pearce, E. J. Metabolic orchestration of the wound healing response. Cell Metab. 33, 1726–1743 (2021).

    Google Scholar 

  17. Amrute, J. M. et al. Targeting immune-fibroblast cell communication in heart failure. Nature 635, 423–433 (2024).

    Google Scholar 

  18. Jiang, Y. et al. Nicotinamide metabolism face-off between macrophages and fibroblasts manipulates the microenvironment in gastric cancer. Cell Metab. 36, 1806–1822.e1811 (2024).

    Google Scholar 

  19. Xu, Y., Ying, L., Lang, J. K., Hinz, B. & Zhao, R. Modeling mechanical activation of macrophages during pulmonary fibrogenesis for targeted anti-fibrosis therapy. Sci. Adv. 10, eadj9559 (2024).

    Google Scholar 

  20. Miao, Y. R., Rankin, E. B. & Giaccia, A. J. Therapeutic targeting of the functionally elusive TAM receptor family. Nat. Rev. Drug Discov. 23, 201–217 (2024).

    Google Scholar 

  21. Rothlin, C. V., Carrera-Silva, E. A., Bosurgi, L. & Ghosh, S. TAM receptor signaling in immune homeostasis. Annu. Rev. Immunol. 33, 355–391 (2015).

    Google Scholar 

  22. Engelmann, J. et al. Regulation of bone homeostasis by MERTK and TYRO3. Nat. Commun. 13, 7689 (2022).

    Google Scholar 

  23. Triantafyllou, E. et al. MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure. Gut 67, 333–347 (2018).

    Google Scholar 

  24. Pan, Z. et al. Inhibition of MERTK reduces organ fibrosis in mouse models of fibrotic disease. Sci. Transl. Med. 16, eadj0133 (2024).

    Google Scholar 

  25. Nerviani, A. et al. Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis. Nat. Commun. 15, 2398 (2024).

    Google Scholar 

  26. Alivernini, S. et al. Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat. Med. 26, 1295–1306 (2020).

    Google Scholar 

  27. Ng, M. T. H. et al. A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution. Nat. Commun. 15, 1394 (2024).

    Google Scholar 

  28. Lantz, C. et al. Early-age efferocytosis directs macrophage arachidonic acid metabolism for tissue regeneration. Immunity 58, 344–361.e347 (2025).

    Google Scholar 

  29. DeBerge, M. et al. Macrophage AXL receptor tyrosine kinase inflames the heart after reperfused myocardial infarction. J. Clin. Investig. 131, https://doi.org/10.1172/JCI139576 (2021).

  30. DeRyckere, D., Huelse, J. M., Earp, H. S. & Graham, D. K. TAM family kinases as therapeutic targets at the interface of cancer and immunity. Nat. Rev. Clin. Oncol. 20, 755–779 (2023).

    Google Scholar 

  31. Wu, H. et al. Mer regulates microglial/macrophage M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury. J. Neuroinflammation 18, 2 (2021).

    Google Scholar 

  32. Myers, K. V., Amend, S. R. & Pienta, K. J. Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment. Mol. Cancer 18, 94 (2019).

    Google Scholar 

  33. Parhiz, H., Atochina-Vasserman, E. N. & Weissman, D. mRNA-based therapeutics: looking beyond COVID-19 vaccines. Lancet 403, 1192–1204 (2024).

    Google Scholar 

  34. Pardi, N. & Krammer, F. mRNA vaccines for infectious diseases—advances, challenges and opportunities. Nat. Rev. Drug Discov. 23, 838–861 (2024).

    Google Scholar 

  35. Shi, Y., Shi, M., Wang, Y. & You, J. Progress and prospects of mRNA-based drugs in pre-clinical and clinical applications. Signal Transduct. Target. Ther. 9, 322 (2024).

    Google Scholar 

  36. Wang, S. et al. Accelerating diabetic wound healing by ROS-scavenging lipid nanoparticle-mRNA formulation. Proc. Natl. Acad. Sci. USA 121, e2322935121 (2024).

    Google Scholar 

  37. Meany, E. L. et al. Generation of an inflammatory niche in a hydrogel depot through recruitment of key immune cells improves efficacy of mRNA vaccines. Sci. Adv. 11, eadr2631 (2025).

    Google Scholar 

  38. Zhu, Y. et al. An mRNA lipid nanoparticle-incorporated nanofiber-hydrogel composite for cancer immunotherapy. Nat. Commun. 16, 5707 (2025).

    Google Scholar 

  39. Cai, B. et al. Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis. Cell Metab. 31, 406–4421.e407 (2020).

    Google Scholar 

  40. Wei, S. et al. Recombinant human epidermal growth factor combined with vacuum sealing drainage for wound healing in Bama pigs. Mil. Med. Res. 8, 18 (2021).

    Google Scholar 

  41. Valenzuela-Silva, C. M. et al. Granulation response and partial wound closure predict healing in clinical trials on advanced diabetes foot ulcers treated with recombinant human epidermal growth factor. Diabetes Care 36, 210–215 (2013).

    Google Scholar 

  42. Maschalidi, S. et al. Targeting SLC7A11 improves efferocytosis by dendritic cells and wound healing in diabetes. Nature 606, 776–784 (2022).

    Google Scholar 

  43. Rurik, J. G. et al. CAR T cells produced in vivo to treat cardiac injury. Science 375, 91–96 (2022).

    Google Scholar 

  44. Yang, T. et al. Preclinical evaluation of AGT mRNA replacement therapy for primary hyperoxaluria type I disease. Sci. Adv. 11, eadt9694 (2025).

    Google Scholar 

  45. Baek, R. et al. Characterizing the mechanism of action for mRNA therapeutics for the treatment of propionic acidemia, methylmalonic acidemia, and phenylketonuria. Nat. Commun. 15, 3804 (2024).

    Google Scholar 

  46. Rohner, E., Yang, R., Foo, K. S., Goedel, A. & Chien, K. R. Unlocking the promise of mRNA therapeutics. Nat. Biotechnol. 40, 1586–1600 (2022).

    Google Scholar 

  47. Bai, X. et al. Optimized inhaled LNP formulation for enhanced treatment of idiopathic pulmonary fibrosis via mRNA-mediated antibody therapy. Nat. Commun. 15, 6844 (2024).

    Google Scholar 

  48. Mascharak, S. et al. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science 372, https://doi.org/10.1126/science.aba2374 (2021).

  49. Mascharak, S. et al. Multi-omic analysis reveals divergent molecular events in scarring and regenerative wound healing. Cell Stem Cell 29, 315–327.e316 (2022).

    Google Scholar 

  50. Griffin, M. F. et al. JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models. Sci. Transl. Med. 13, eabb3312 (2021).

    Google Scholar 

  51. Wculek, S. K. et al. Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis. Immunity 56, 516–530 e519 (2023).

    Google Scholar 

  52. Du, L. et al. IGF-2 preprograms maturing macrophages to acquire oxidative phosphorylation-dependent anti-inflammatory properties. Cell Metab. 29, 1363–1375.e1368 (2019).

    Google Scholar 

  53. Mehrotra, P. & Ravichandran, K. S. Drugging the efferocytosis process: concepts and opportunities. Nat. Rev. Drug Discov. 21, 601–620 (2022).

    Google Scholar 

  54. Guo, Q. et al. NF-kappaB in biology and targeted therapy: new insights and translational implications. Signal Transduct. Target. Ther. 9, 53 (2024).

    Google Scholar 

  55. Bahar, M. E., Kim, H. J. & Kim, D. R. Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Signal Transduct. Target. Ther. 8, 455 (2023).

    Google Scholar 

  56. Li, Y. et al. Exploring TNFR1: from discovery to targeted therapy development. J. Transl. Med. 23, 71 (2025).

    Google Scholar 

  57. Erlandsson, M. C. et al. IGF-1R signalling contributes to IL-6 production and T cell dependent inflammation in rheumatoid arthritis. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 2158–2170 (2017).

    Google Scholar 

  58. Jere, S. W., Houreld, N. N. & Abrahamse, H. Role of the PI3K/AKT (mTOR and GSK3beta) signalling pathway and photobiomodulation in diabetic wound healing. Cytokine Growth Factor Rev. 50, 52–59 (2019).

    Google Scholar 

  59. Kefaloyianni, E. et al. Proximal tubule-derived amphiregulin amplifies and integrates profibrotic EGF receptor signals in kidney fibrosis. J. Am. Soc. Nephrol. 30, 2370–2383 (2019).

    Google Scholar 

  60. Li, H. et al. Upregulation of HER2 in tubular epithelial cell drives fibroblast activation and renal fibrosis. Kidney Int. 96, 674–688 (2019).

    Google Scholar 

  61. Zhang, F. et al. A dynamically phase-adaptive regulating hydrogel promotes ultrafast anti-fibrotic wound healing. Nat. Commun. 16, 3738 (2025).

    Google Scholar 

  62. Zhang, Y. et al. Scarless wound healing programmed by core-shell microneedles. Nat. Commun. 14, 3431 (2023).

    Google Scholar 

  63. Zhang, J. et al. A pulsatile release platform based on photo-induced imine-crosslinking hydrogel promotes scarless wound healing. Nat. Commun. 12, 1670 (2021).

    Google Scholar 

  64. Chen, R. et al. A+T rich interaction domain protein 3a (Arid3a) impairs Mertk-mediated efferocytosis in cholestasis. J. Hepatol. 79, 1478–1490 (2023).

    Google Scholar 

  65. Chan, P. Y. et al. The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity. Science 352, 99–103 (2016).

    Google Scholar 

  66. Li, X. et al. A calcitonin gene-related peptide co-crosslinked hydrogel promotes diabetic wound healing by regulating M2 macrophage polarization and angiogenesis. Acta Biomater. 196, 109–122 (2025).

    Google Scholar 

  67. Kim, D. H. et al. Inhibition of AXL ameliorates pulmonary fibrosis via attenuation of M2 macrophage polarization. Eur Respir J. https://doi.org/10.1183/13993003.00615-2024 (2025).

  68. Fourcot, A. et al. Gas6 deficiency prevents liver inflammation, steatohepatitis, and fibrosis in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G1043–G1053 (2011).

    Google Scholar 

  69. Chen, Z. et al. Engineered enucleated mesenchymal stem cells regulating immune microenvironment and promoting wound healing. Adv. Mater. 36, e2412253 (2024).

    Google Scholar 

  70. Lin, Y. et al. Tissue-specific mRNA delivery and prime editing with peptide-ionizable lipid nanoparticles. Nat. Mater. https://doi.org/10.1038/s41563-025-02320-9 (2025).

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