Abstract
Deep cutaneous injuries in adult mammals often lead to fibrotic scarring, a process exacerbated by inflammatory fibroblasts that amplify immune recruitment. Early modulation of immune–fibroblast crosstalk represents a promising therapeutic strategy. Here we show that GAS6 is a key regulator of this interaction and can be therapeutically targeted using a spatiotemporally controlled lipid nanoparticle (LNP)–mRNA hydrogel platform. We engineer LNP-GAS6 mRNA to enhance macrophage efferocytosis and suppress inflammatory fibroblasts, then encapsulate it in a thermosensitive hydrogel for localized delivery. In murine, rabbit ear, and Bama minipig wound models, this treatment significantly accelerates wound closure and reduces fibrotic scarring. These results demonstrate that restoring GAS6 signaling via mRNA-based delivery promotes scarless healing and offers an effective therapeutic approach for fibrotic skin disorders.
Data availability
The RNA-seq data generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) database under accession codes GSE283228 and GSE309507. The GSE283228 and GSE309507 datasets are publicly accessible. The previously published sequencing data analyzed in this study are available in the GEO database under accession codes GSE113619, GSE178411, GSE53986, GSE241132, and GSE186527. Source data are provided with this paper.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (grant 82272296 to C.Y., grant 82472552 to C.Y., grant 82402927 to Y.Z., grant 82470654 to Z.R., grant 82570691 to Z.R.), the Zhejiang University School of Medicine Affiliated Second Hospital start-up funds (Y199532022 to C.Y.), and the Central Guidance on Local Science and Technology Development Fund of Zhejiang Province (2024ZY01006 to Z.M.). The authors thank the Analysis Center of Agrobiology and Environmental Sciences & Institute of Agrobiology and Environmental Sciences, Zhejiang University, for their technical assistance with Transmission Electron Microscopy.
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Y.H., K.Y., and Y.Z. contributed equally to this study. Y.H. and C.Y. conceived and designed the experiments. Y.H., K.Y., and Y.Z. performed most of the experiments. Z.C., H.S., and P.G. performed part of the animal experiments. G.C, Z.C., H.S., and H.Y. provided technical and material support. Y.H., K.Y., and Y.Z. analyzed data and drafted the manuscript. Z.R., Y.H., and C.Y. initiated the study and reviewed the manuscript. H.Y., Z.M., and C.Y. supervised the project. All authors have read and approved the article.
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He, Y., Ye, K., Zhang, Y. et al. Spatiotemporally controlled restoration of GAS6 signaling via mRNA therapy promotes scarless healing in preclinical models. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69540-8
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DOI: https://doi.org/10.1038/s41467-026-69540-8
