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The poly-(HA-GMA) hydrogel carrying AAV8-sTβRII alleviates scar formation in mice skin wound healing by inhibiting fibrosis

Gene Therapy (2026)Cite this article

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Abstract

Effective scar control requires selectively suppressing late-stage fibrosis without compromising early wound closure. We developed a localized, time-staged delivery system. A poly-(HA-GMA) hydrogel serves as a short-term depot, loaded with AAV8-sTβRII and applied directly along the wound margin. Materials characterization showed a water-rich porous network that rapidly imbibes and releases vector primarily by diffusion. In vivo, the hydrogel naturally degrades in ~3 days, enabling local enrichment in early healing without excessive retention. In a mouse full-thickness skin-wound model, this approach achieved efficient transduction of the cutaneous and fascial layers while markedly reducing hepatic exposure. From postoperative day 6 onward it accelerated closure and produced a thinner dermis, more orderly collagen organization, and a lower collagen area fraction. Mechanistically, Flag-sTβRII was detected within scar tissue. Phospho-Smad2/3 and α-SMA were reduced, whereas total Smad2/3 was largely unchanged, indicating that inhibition occurs at the activation step of the TGF-β/Smad pathway. Moreover, adding exogenous TGF-β1 reversed the macroscopic and histological benefits, strengthening the evidence for pathway specificity. Compared with direct intradermal injection, hydrogel delivery simultaneously increased local expression and limited systemic spillover. Using the AAV8 capsid provided the most favorable balance—high in skin, low in liver. Safety readouts—including body weight, serum transaminases, and histology of major organs—showed no abnormalities. To our knowledge, the “HA-GMA × AAV8-sTβRII” strategy precisely aligns pathway antagonism with the escalation phase of fibrosis, yielding improvements from molecular and cellular phenotypes to tissue remodeling and healing. It offers a generalizable, materials–biology integrated platform for anti-fibrotic gene therapy at the wound edge.

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Fig. 1: In vivo transduction profile on day 7 after intradermal injection of different AAV serotypes.
Fig. 2: In vivo and ex vivo bioluminescence imaging and quantification on day 21 after intradermal injection of different AAV serotypes.
Fig. 3: Preparation of poly-(HA-GMA) hydrogels and characterization of drug loading and release.
Fig. 4: Imaging and quantification of different AAV serotypes delivered via poly-(HA-GMA) hydrogel in mouse skin wounds.
Fig. 5: Evaluation of localization and tissue distribution: poly-(HA-GMA) hydrogel delivery versus direct injection.
Fig. 6: Wound healing and histological evaluation of AAV8-sTβRII delivered via poly-(HA-GMA) hydrogel.
Fig. 7: Delivery of AAV8-sTβRII via poly-(HA-GMA) hydrogel suppresses TGF-β/Smad signaling and reduces skin scarring; a TGF-β1 rescue experiment confirms pathway specificity.
Fig. 8: Overall safety assessment of AAV8-sTβRII delivery via poly-(HA-GMA) hydrogel.

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Data availability

All data generated and/or analyzed during this study are included in this published article and its supplementary information files. The raw data supporting the findings of this study (including, but not limited to, original Western blot images, histological images, and quantitative analysis data) are available from the corresponding author upon reasonable request.

References

  1. Jeschke MG, Wood FM, Middelkoop E, Bayat A, Teot L, Ogawa R, et al. Scars. Nat Rev Dis Prim. 2023;9:64.

    Article  PubMed  Google Scholar 

  2. Deng Z, Fan T, Xiao C, Tian H, Zheng Y, Li C, et al. TGF-β signaling in health, disease, and therapeutics. Signal Transduct Target Ther. 2024;9:61.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Massagué J, Sheppard D. TGF-β signaling in health and disease. Cell. 2023;186:4007–37.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Martin P, Pardo-Pastor C, Jenkins RG, Rosenblatt J. Imperfect wound healing sets the stage for chronic diseases. Science. 2024;386:eadp2974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Reiss UM, Davidoff AM, Tuddenham EGD, Chowdary P, McIntosh J, Muczynski V, et al. Sustained clinical benefit of AAV gene therapy in severe hemophilia B. N Engl J Med. 2025;392:2226–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ponomarev A, Ganiev I, Aimaletdinov A, Mansurova M, Titova A, Rizvanov A, et al. Evaluation of the efficacy of transglutaminase 1 gene delivery by adeno-associated virus into rat and pig skin and safety of ARCI gene therapy. Int J Mol Sci. 2025;26:9976.

  7. Wang JH, Gessler DJ, Zhan W, Gallagher TL, Gao G. Adeno-associated virus as a delivery vector for gene therapy of human diseases. Signal Transduct Target Ther. 2024;9:78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. McCarty DM, Monahan PE, Samulski RJ. Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis. Gene Ther. 2001;8:1248–54.

    Article  CAS  PubMed  Google Scholar 

  9. Correa-Gallegos D, Ye H, Dasgupta B, Sardogan A, Kadri S, Kandi R, et al. CD201(+) fascia progenitors choreograph injury repair. Nature. 2023;623:792–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dabelsteen S, Pallesen EMH, Marinova IN, Nielsen MI, Adamopoulou M, Rømer TB, et al. Essential functions of glycans in human epithelia dissected by a CRISPR-Cas9-engineered human organotypic skin model. Dev Cell. 2020;54:669–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Meyer NL, Chapman MS. Adeno-associated virus (AAV) cell entry: structural insights. Trends Microbiol. 2022;30:432–51.

    Article  CAS  PubMed  Google Scholar 

  12. Kato M, Ishikawa S, Shen Q, Du Z, Katashima T, Naito M, et al. In situ-formable, dynamic crosslinked poly(ethylene glycol) carrier for localized adeno-associated virus infection and reduced off-target effects. Commun Biol. 2023;6:508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li J, Celiz AD, Yang J, Yang Q, Wamala I, Whyte W, et al. Tough adhesives for diverse wet surfaces. Science. 2017;357:378–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Li J, Mooney DJ Designing hydrogels for controlled drug delivery. Nat Rev Mater. 2016;1:16071.

  15. Weng L, Gouldstone A, Wu Y, Chen W. Mechanically strong double network photocrosslinked hydrogels from N,N-dimethylacrylamide and glycidyl methacrylated hyaluronan. Biomaterials. 2008;29:2153–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Spearman BS, Agrawal NK, Rubiano A, Simmons CS, Mobini S, Schmidt CE. Tunable methacrylated hyaluronic acid-based hydrogels as scaffolds for soft tissue engineering applications. J Biomed Mater Res A. 2020;108:279–91.

    Article  CAS  PubMed  Google Scholar 

  17. Mascarenhas J, Migliaccio AR, Kosiorek H, Bhave R, Palmer J, Kuykendall A, et al. A phase Ib trial of AVID200, a TGFβ 1/3 Trap, in patients with myelofibrosis. Clin Cancer Res. 2023;29:3622–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schirmer L, Atallah P, Freudenberg U, Werner C. Chemokine-capturing wound contact layer rescues dermal healing. Adv Sci. 2021;8:e2100293.

    Article  Google Scholar 

  19. Liu X, Zhuang Y, Huang W, Wu Z, Chen Y, Shan Q, et al. Interventional hydrogel microsphere vaccine as an immune amplifier for activated antitumour immunity after ablation therapy. Nat Commun. 2023;14:4106.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Fajardo AR, Fávaro SL, Rubira AF, Muniz EC. Dual-network hydrogels based on chemically and physically crosslinked chitosan/chondroitin sulfate. React Funct Polym. 2013;73:1662–71.

    Article  CAS  Google Scholar 

  21. Penaud-Budloo M, François A, Clément N, Ayuso E. Pharmacology of recombinant adeno-associated virus production. Mol Ther Methods Clin Dev. 2018;8:166–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang H, Li R, Sadekar S, Kamath AV, Shen BQ. A novel approach to quantitate biodistribution and transduction of adeno-associated virus gene therapy using radiolabeled AAV vectors in mice. Mol Ther Methods Clin Dev. 2024;32:101326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Correa S, Grosskopf AK, Lopez Hernandez H, Chan D, Yu AC, Stapleton LM, et al. Translational applications of hydrogels. Chem Rev. 2021;121:11385–457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Richbourg NR, Peppas NA. The swollen polymer network hypothesis: quantitative models of hydrogel swelling, stiffness, and solute transport. Prog Polym Sci. 2020;105:101243.

    Article  CAS  Google Scholar 

  25. Wu F, Pang Y, Liu J. Swelling-strengthening hydrogels by embedding with deformable nanobarriers. Nat Commun. 2020;11:4502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kim D, Lu N, Ma R, Kim Y, Kim R, Wang S, et al. Epidermal electronics. Science. 2011;333:838–43.

    Article  CAS  PubMed  Google Scholar 

  27. Chu M, Nguyen T, Pandey V, Zhou Y, Pham HN, Bar-Yoseph R, et al. Respiration rate and volume measurements using wearable strain sensors. npj Digit Med. 2019;2:8.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Jensen KH, Kim W, Chang S. Dynamics of water imbibition through hydrogel-coated capillary tubes. Phys Rev Fluids. 2022;7:64301.

    Article  Google Scholar 

  29. Huang X, Brazel CS. On the importance and mechanisms of burst release in matrix-controlled drug delivery systems. J Control Release. 2001;73:121–36.

    Article  CAS  PubMed  Google Scholar 

  30. Ashcroft GS, Dodsworth J, van, Boxtel E, Tarnuzzer RW, Horan MA, et al. Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta1 levels. Nat Med. 1997;3:1209–15.

    Article  CAS  PubMed  Google Scholar 

  31. Butzelaar L, Ulrich MM, Mink van der Molen AB, Niessen FB, Beelen RH. Currently known risk factors for hypertrophic skin scarring: a review. J Plast Reconstr Aesthet Surg. 2016;69:163–9.

    Article  CAS  PubMed  Google Scholar 

  32. Lim CH, Sun Q, Ratti K, Lee SH, Zheng Y, Takeo M, et al. Hedgehog stimulates hair follicle neogenesis by creating inductive dermis during murine skin wound healing. Nat Commun. 2018;9:4903.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Nuutila K, Eriksson E. Moist wound healing with commonly available dressings. Adv Wound Care. 2021;10:685–98.

    Article  Google Scholar 

  34. Chen JH, Zhan LJ, Lv CM, Teng JB, Cao CY. Advances and challenges in adeno-associated virus gene therapy applications of localized delivery strategies. Curr Med Sci. 2025;45:683–98.

    Article  PubMed  Google Scholar 

  35. Walkey CJ, Snow KJ, Bulcha J, Cox AR, Martinez AE, Ljungberg MC, et al. A comprehensive atlas of AAV tropism in the mouse. Mol Ther. 2025;33:1282–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yang Y, Chu C, Liu L, Wang C, Hu C, Rung S, et al. Tracing immune cells around biomaterials with spatial anchors during large-scale wound regeneration. Nat Commun. 2023;14:5995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rajendran V, Ramesh P, Dai R, Kalgudde Gopal S, Ye H, Machens HG, et al. Therapeutic silencing of p120 in fascia fibroblasts ameliorates tissue repair. J Investig Dermatol. 2023;143:854–63.

    Article  CAS  PubMed  Google Scholar 

  38. Greig JA, Martins KM, Breton C, Lamontagne RJ, Zhu Y, He Z, et al. Integrated vector genomes may contribute to long-term expression in primate liver after AAV administration. Nat Biotechnol. 2024;42:1232–42.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work is supported by The central government guides the special funds for the development of local science and technology (2024BSB012) and the National Natural Science Foundation of China (81772833) and Hubei Provincial Natural Science Foundation of China (2024AFB585). The authors would like to thank Shuchu Shen for helping with the modification of the figure.

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Author notes

  1. These authors contributed equally: Jinhao Chen, Lijun Zhan, Jinyan Duan.

Authors and Affiliations

  1. Hubei Provincial Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang, China

    Jinhao Chen, Lijun Zhan, Jinyan Duan, Tianning Wang, Zenan Meng, Qianru Wang, Jianlin Yang, Xiaofei Huang, Yue Liao & Chunyu Cao

  2. Affiliated Renhe Hospital of China Three Gorges University, Yichang, China

    Jinhao Chen, Zenan Meng, Qianru Wang, Xiaofei Huang & Chunyu Cao

  3. Clinical Medical Research Center for Precision Diagnosis and Treatment of Lung Cancer and Management of Advanced Cancer Pain of Hubei Province, the First College of Clinical Medical Science, China Three Gorges University, Yichang, China

    Xinyu Song & Chunyu Cao

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Contributions

JC conceived the study and contributed to methodology, data curation, and writing of the original draft. LZ, JD, and TW contributed to software and writing of the original draft. ZM., QW, and JY contributed to visualization, software, and investigation. XH contributed to data curation. YL contributed to supervision, software, and resources. XS and CC contributed to writing—review and editing, supervision, and funding acquisition. All authors reviewed and approved the final manuscript.

Corresponding authors

Correspondence to Yue Liao, Xinyu Song or Chunyu Cao.

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Ethical approval

All animal experiments in this study were approved by the Animal Ethics Committee of China Three Gorges University (Approval No. 2024020H1). All experimental procedures were performed in strict accordance with relevant institutional and national guidelines and regulations for the care and use of laboratory animals. All methods were carried out in accordance with relevant guidelines and regulations.

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The authors have declared that no competing interests exist.

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Chen, J., Zhan, L., Duan, J. et al. The poly-(HA-GMA) hydrogel carrying AAV8-sTβRII alleviates scar formation in mice skin wound healing by inhibiting fibrosis. Gene Ther (2026). https://doi.org/10.1038/s41434-026-00608-2

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