{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:58:51Z","timestamp":1785405531311,"version":"3.56.0"},"reference-count":49,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173731"],"award-info":[{"award-number":["82173731"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82173731"],"award-info":[{"award-number":["82173731"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Shanghai","award":["21ZR1427300"],"award-info":[{"award-number":["21ZR1427300"]}]},{"name":"Shanghai Innovation Action Plan","award":["19440741200"],"award-info":[{"award-number":["19440741200"]}]},{"name":"General Scientific Research Project of Zhejiang Provincial Department of Education","award":["Y201942436"],"award-info":[{"award-number":["Y201942436"]}]},{"name":"Foundation of Zhejiang Key Laboratory of Multiomics and Molecular Enzymology","award":["2025YB006"],"award-info":[{"award-number":["2025YB006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gels"],"abstract":"<jats:p>Impaired wound healing is often caused by persistent inflammation, bacterial infection, and insufficient extracellular matrix remodeling. Natural polymer-based hydrogels represent ideal wound dressings but often struggle to balance structural stability and biological activity. Herein, we report a dual-functional network regulation strategy enabled by highly soluble mussel foot protein (HMFP) that acts simultaneously as a structural crosslinking regulator and bioactive effector to fabricate synergistic hydrogels (CS-SH-H) from \u03b2-chitosan (CS) and sodium hyaluronate (SH). HMFP homogenizes the porous microstructure, strengthens intermolecular interactions, and significantly improves thermal and structural stability via multivalent non-covalent bonding. In vitro, CS-SH-H shows excellent cytocompatibility, significantly promotes fibroblast proliferation and migration, and exerts potent antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). In a mouse full-thickness skin defect model, the hydrogel dramatically accelerates wound closure, reducing the residual wound area to 25% on day 7, outperforming the control groups. Immunohistochemistry confirms that HMFP suppresses TNF-\u03b1-mediated inflammation and enhances Ki-67-positive cell proliferation, leading to accelerated re-epithelialization and collagen deposition. This study establishes HMFP as a promising marine-derived dual-functional network regulator for designing high-performance hydrogel dressings. This strategy is scalable and translatable for treating infected and inflammatory wounds.<\/jats:p>","DOI":"10.3390\/gels12070627","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T10:12:53Z","timestamp":1784023973000},"page":"627","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synergistic Hydrogels Enabled by Dual-Regulatory Mussel Foot Protein for Advancing Wound Healing"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3048-1393","authenticated-orcid":false,"given":"Jiren","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6360-1169","authenticated-orcid":false,"given":"Chen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4115-9918","authenticated-orcid":false,"given":"Jeevithan","family":"Elango","sequence":"additional","affiliation":[{"name":"Department of Biomaterials Engineering, Faculty of Health Sciences, UCAM-Universidad Cat\u00f3lica San Antonio de Murcia, Campus de los Jer\u00f3nimos 135, Guadalupe, 30107 Murcia, Spain"},{"name":"Center of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Institute of Medical and Technical Sciences, Saveetha Dental College and Hospitals, Saveetha University, Chennai 600077, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1710-8582","authenticated-orcid":false,"given":"Wenhui","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"},{"name":"Putuo Branch of International Combined Research Center for Marine Biological Sciences, Zhoushan 316104, China"},{"name":"Marine Biomedical Science and Technology Innovation Platform of Lin-gang Special Area, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Fu","sequence":"additional","affiliation":[{"name":"College of Foreign Languages, Ningbo University of Finance & Economics, Ningbo 315175, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9033-4367","authenticated-orcid":false,"given":"Bailei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biomedicine, Zhejiang Key Laboratory of Multiomics and Molecular Enzymology, Yangtze Delta Region Institute of Tsinghua University (Zhejiang), Jiaxing 314006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Baker, P., Huang, C., Radi, R., Moll, S.B., Jules, E., and Arbiser, J.L. (2023). Skin Barrier Function: The Interplay of Physical, Chemical, and Immunologic Properties. Cells, 12.","DOI":"10.3390\/cells12232745"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.mucimm.2023.02.005","article-title":"Skin Barrier Immunology from Early Life to Adulthood","volume":"16","author":"Trompette","year":"2023","journal-title":"Mucosal Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1111\/jocd.16155","article-title":"Skin Homeostasis: Mechanism and Influencing Factors","volume":"23","author":"Jiao","year":"2024","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"109532","DOI":"10.1016\/j.isci.2024.109532","article-title":"Infection Induced Inflammation Impairs Wound Healing through IL-1\u03b2 Signaling","volume":"27","author":"Shen","year":"2024","journal-title":"iScience"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/s41580-024-00715-1","article-title":"Cellular and Molecular Mechanisms of Skin Wound Healing","volume":"25","author":"Martin","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Br\u00fcning-Richardson, A., and Knipp, S. (2024). Cell Migration in Wound Healing. Cell Migration in Development, Health and Disease, Springer Nature.","DOI":"10.1007\/978-3-031-64532-7"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e70602","DOI":"10.1002\/mco2.70602","article-title":"Applications of Multifunctional Hydrogel in Tissue Engineering and Regenerative Medicine","volume":"7","author":"Lyu","year":"2026","journal-title":"MedComm"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/s41578-024-00693-y","article-title":"Wound Management Materials and Technologies from Bench to Bedside and Beyond","volume":"9","author":"Wang","year":"2024","journal-title":"Nat. Rev. Mater."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4827","DOI":"10.1021\/acs.molpharmaceut.4c00595","article-title":"Hydrogels as a Potential Biomaterial for Multimodal Therapeutic Applications","volume":"21","author":"Kaur","year":"2024","journal-title":"Mol. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s44347-025-00017-5","article-title":"Advances in Natural Polymer-Based Hydrogels: Synthesis, Applications, and Future Directions in Biomedical and Environmental Fields","volume":"2","author":"Nanda","year":"2025","journal-title":"Discov. Polym."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Moreno, J.M.C., Chelu, M., and Popa, M. (2025). Biocompatible Stimuli-Sensitive Natural Hydrogels: Recent Advances in Biomedical Applications. Gels, 11.","DOI":"10.3390\/gels11120993"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s44328-025-00055-w","article-title":"Emerging Roles of Hydrogels, Organogels, and Their Hybrids in Soft Bioelectronics and Bioplatforms","volume":"2","author":"Lee","year":"2025","journal-title":"npj Biosens."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1002\/bit.27339","article-title":"Enhanced Production of Dopa-Incorporated Mussel Adhesive Protein Using Engineered Translational Machineries","volume":"117","author":"Jeong","year":"2020","journal-title":"Biotechnol. Bioeng."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6097","DOI":"10.1021\/acsbiomaterials.4c01378","article-title":"Advances in Mussel Adhesion Proteins and Mussel-Inspired Material Electrospun Nanofibers for Their Application in Wound Repair","volume":"10","author":"Dai","year":"2024","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"146609","DOI":"10.1016\/j.ijbiomac.2025.146609","article-title":"Mussel Foot Protein with Genetically Incorporated Hydroxyproline and DOPA Exhibits Enhanced Phase Separation and Underwater Adhesion","volume":"322","author":"Valappil","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8663","DOI":"10.1038\/ncomms9663","article-title":"High-Performance Mussel-Inspired Adhesives of Reduced Complexity","volume":"6","author":"Ahn","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3605","DOI":"10.1039\/C9CS00849G","article-title":"Mussel-Inspired Hydrogels: From Design Principles to Promising Applications","volume":"49","author":"Zhang","year":"2020","journal-title":"Chem. Soc. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.eng.2024.02.005","article-title":"A Polyvinyl Alcohol\/Acrylamide Hydrogel with Enhanced Mechanical Properties Promotes Full-Thickness Skin Defect Healing by Regulating Immunomodulation and Angiogenesis Through Paracrine Secretion","volume":"37","author":"Wang","year":"2024","journal-title":"Engineering"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"109483","DOI":"10.1016\/j.porgcoat.2025.109483","article-title":"Mussel Inspired Polysiloxane Coatings with Tunable Surface Morphology for Enhanced Marine Antibiofilm Performance","volume":"208","author":"Chen","year":"2025","journal-title":"Prog. Org. Coat."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"141988","DOI":"10.1016\/j.ijbiomac.2025.141988","article-title":"Molecular Simulations Guiding Recombinant Mussel Protein with Enhanced Applicable Properties for Adhesive Materials","volume":"307","author":"Xue","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4967","DOI":"10.1021\/acs.biomac.5c00382","article-title":"Mussel Foot-Inspired Multifunctional Engineered Protein Adhesive with Enhanced Antibacterial Properties","volume":"26","author":"Xu","year":"2025","journal-title":"Biomacromolecules"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1002\/pro.2147","article-title":"Three Intrinsically Unstructured Mussel Adhesive Proteins, Mfp-1, Mfp-2, and Mfp-3: Analysis by Circular Dichroism","volume":"21","author":"Hwang","year":"2012","journal-title":"Protein Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.ijbiomac.2022.11.147","article-title":"Promoting Soluble Expression of Hybrid Mussel Foot Proteins by SUMO-TrxA Tags for Production of Mussel Glue","volume":"225","author":"Wang","year":"2023","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.jbiosc.2023.05.002","article-title":"Functional Modification of Mussel Adhesive Protein to Control Solubility and Adhesion Property","volume":"136","author":"Nakashima","year":"2023","journal-title":"J. Biosci. Bioeng."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"112973","DOI":"10.1016\/j.colsurfb.2022.112973","article-title":"A Review of Protein Hydrogels: Protein Assembly Mechanisms, Properties, and Biological Applications","volume":"220","author":"Tang","year":"2022","journal-title":"Colloids Surf. B"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Katona, G., Sipos, B., and Cs\u00f3ka, I. (2025). Advancements in the Field of Protein-Based Hydrogels: Main Types, Characteristics, and Their Applications. Gels, 11.","DOI":"10.3390\/gels11050306"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1007\/s42452-025-07780-x","article-title":"Collagen and Collagen-Derived Materials: Synthesis, Structure, Classification, Fundamental Properties and Biomedical Applications","volume":"7","author":"Emam","year":"2025","journal-title":"Discov. Appl. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ma, X., Chuang, P.-H., Tseng, Y.-H., Wang, X., Ma, Z., Chen, H., Zhai, W., Yang, W., Meng, Z., and Xu, J. (2025). Progress in Research on Animal Collagen Peptides: Preparation, Bioactivity, and Application. Molecules, 30.","DOI":"10.3390\/molecules30153061"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6653","DOI":"10.1039\/D1BM01126J","article-title":"Recent Developments in Mussel-Inspired Materials for Biomedical Applications","volume":"9","author":"Barros","year":"2021","journal-title":"Biomater. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ma, Y., Zhang, B., Frenkel, I., Zhang, Z., Pei, X., Zhou, F., and He, X. (2021). Mussel-Inspired Underwater Adhesives-from Adhesion Mechanisms to Engineering Applications: A Critical Review. Progress in Adhesion and Adhesives, John Wiley & Sons, Ltd.","DOI":"10.1002\/9781119846703.ch17"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Cui, G., Guo, X., Su, P., Zhang, T., Guan, J., and Wang, C. (2023). Mussel-Inspired Nanoparticle Composite Hydrogels for Hemostasis and Wound Healing. Front. Chem., 11.","DOI":"10.3389\/fchem.2023.1154788"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0167-7799(90)90134-J","article-title":"Protein-Based Medical Adhesives","volume":"8","author":"Strausberg","year":"1990","journal-title":"Trends Biotechnol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Li, N., Xu, J., Liu, B., Elango, J., and Wu, W. (2025). Highly Soluble Mussel Foot Protein Enhances Antioxidant Defense and Cytoprotection via PI3K\/Akt and Nrf2\/HO-1 Pathways. Antioxidants, 14.","DOI":"10.3390\/antiox14060644"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Li, B., Elango, J., and Wu, W. (2020). Recent Advancement of Molecular Structure and Biomaterial Function of Chitosan from Marine Organisms for Pharmaceutical and Nutraceutical Application. Appl. Sci., 10.","DOI":"10.3390\/app10144719"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Li, B., Wu, X., Bao, B., Guo, R., and Wu, W. (2021). Evaluation of \u03b1-Chitosan from Crab Shell and \u03b2-Chitosan from Squid Gladius Based on Biochemistry Performance. Appl. Sci., 11.","DOI":"10.3390\/app11073183"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"132351","DOI":"10.1016\/j.ijbiomac.2024.132351","article-title":"Synthesis of Novel Chitosan\/Sodium Hyaluronate\/Iridium Hydrogel Nanocomposite for Wound Healing Application","volume":"270","author":"Chen","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"101270","DOI":"10.1016\/j.nxmate.2025.101270","article-title":"Chitosan and Its Biomedical Applications: A Review","volume":"9","author":"Saputra","year":"2025","journal-title":"Next Mater."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"18225","DOI":"10.1021\/acsami.9b22120","article-title":"Dopamine-Modified Hyaluronic Acid Hydrogel Adhesives with Fast-Forming and High Tissue Adhesion","volume":"12","author":"Zhou","year":"2020","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3619","DOI":"10.1021\/acsbiomaterials.0c00545","article-title":"Thermoresponsive Chitosan\/DOPA-Based Hydrogel as an Injectable Therapy Approach for Tissue-Adhesion and Hemostasis","volume":"6","author":"Shou","year":"2020","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"10748","DOI":"10.1039\/D1NR02065J","article-title":"Effects of Polyethylene Glycol on the Surface of Nanoparticles for Targeted Drug Delivery","volume":"13","author":"Shi","year":"2021","journal-title":"Nanoscale"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Li, N., Li, Y., Xu, J., Elango, J., and Wu, W. (2025). Highly Soluble Mussel Foot Protein and Its Derivatives Inhibit Inflammation by Targeting NF-\u03baB\/PI3K-Akt Signaling and Promoting M2 Macrophage Polarization. Antioxidants, 14.","DOI":"10.3390\/antiox14081021"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8887","DOI":"10.1021\/acs.macromol.8b01658","article-title":"Elastic\u2013Plastic Transformation of Polyelectrolyte Complex Hydrogels from Chitosan and Sodium Hyaluronate","volume":"51","author":"Shi","year":"2018","journal-title":"Macromolecules"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"119403","DOI":"10.1016\/j.carbpol.2022.119403","article-title":"Dynamic Behavior of Tough Polyelectrolyte Complex Hydrogels from Chitosan and Sodium Hyaluronate","volume":"288","author":"Liu","year":"2022","journal-title":"Carbohydr. Polym."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Dou, W., Zeng, X., Zhu, S., Zhu, Y., Liu, H., and Li, S. (2024). Mussel-Inspired Injectable Adhesive Hydrogels for Biomedical Applications. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25169100"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Chen, Y., Cao, Y., Cui, P., and Lu, S. (2025). Mussel-Inspired Hydrogel Applied to Wound Healing: A Review and Future Prospects. Biomimetics, 10.","DOI":"10.3390\/biomimetics10040206"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8084","DOI":"10.1038\/s41598-022-12150-3","article-title":"Antimicrobial Properties of Chitosan from Different Developmental Stages of the Bioconverter Insect Hermetia illucens","volume":"12","author":"Guarnieri","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"134321","DOI":"10.1016\/j.ijbiomac.2024.134321","article-title":"Factors Influencing the Antimicrobial Mechanism of Chitosan Action and Its Derivatives: A Review","volume":"277","author":"Nasaj","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1053\/j.semdp.2024.05.001","article-title":"Review of Immunohistochemistry Techniques: Applications, Current Status, and Future Perspectives","volume":"41","author":"Mebratie","year":"2024","journal-title":"Semin. Diagn. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e2300359","DOI":"10.1002\/smll.202300359","article-title":"Safe and Durable Treatment of Dentin Hypersensitivity via Nourishing and Remineralizing Dentin Based on \u03b2-Chitooligosaccharide Graft Derivative","volume":"19","author":"Li","year":"2023","journal-title":"Small"}],"container-title":["Gels"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2310-2861\/12\/7\/627\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T10:43:20Z","timestamp":1784025800000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2310-2861\/12\/7\/627"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,14]]},"references-count":49,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["gels12070627"],"URL":"https:\/\/doi.org\/10.3390\/gels12070627","relation":{},"ISSN":["2310-2861"],"issn-type":[{"value":"2310-2861","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,14]]}}}