{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T04:29:41Z","timestamp":1786768181898,"version":"build-2736575974"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100019266","name":"Korea Medical Device Development Fund","doi-asserted-by":"crossref","award":["2410018879, RS-2026-25545758"],"award-info":[{"award-number":["2410018879, RS-2026-25545758"]}],"id":[{"id":"10.13039\/100019266","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2410018879, RS-2026-25545758"],"award-info":[{"award-number":["2410018879, RS-2026-25545758"]}],"id":[{"id":"https:\/\/ror.org\/03g98ap29","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Loss of epithelial integrity leaves the wound bed open to opportunistic bacterial colonization, and the risk of secondary infection persists for as long as the defect remains unclosed. Wound dressings must therefore provide an immediate external barrier while accelerating restoration of the skin\u2019s own barrier. This study aims to develop and evaluate a bioactive nanotechnological platform comprising dexpanthenol (Dxp)-engineered extracellular vesicles (EVs) embedded within cross-linked hyaluronic acid hydrogels (HA@Dxp-engineered EVs) for targeted wound treatment and protection against external contaminants. Methods: EVs were engineered via exogenous (extrusion; Exo EV) and endogenous (co-incubation; Endo EV) strategies to encapsulate Dxp. The physicochemical properties of the HA@Dxp-engineered EV systems were characterized, and their therapeutic efficacy was validated through in vitro assays, including fibroblast migration and endothelial tube formation, and in vivo using a full-thickness excisional wound model in mice. Results: Both engineering strategies successfully encapsulated Dxp while preserving the structural integrity of the EVs. The HA hydrogel enabled sustained EV release and provided a physical barrier. In vitro, HA@Endo EVs significantly promoted fibroblast proliferation, migration, and the formation of mature capillary-like networks in HUVECs compared to controls. In vivo, the HA@Endo EV group demonstrated accelerated wound closure, achieving 99.88% healing by day 10, and promoted tissue remodeling with upregulated expression of COL1A1, VEGF, and HIF-1\u03b1. Conclusions: The HA@Endo EV system provides a dual-action strategy against secondary infection risk. It supplies an immediate physical barrier over the wound bed and simultaneously accelerates re-epithelialization, thereby shortening the interval during which the tissue remains exposed.<\/jats:p>","DOI":"10.3390\/pharmaceutics18081003","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T17:01:35Z","timestamp":1786640495000},"page":"1003","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hyaluronic Acid Hydrogel Incorporating Dexpanthenol-Engineered Extracellular Vesicles for Accelerated Wound Closure and Mitigated Secondary Infection Risk"],"prefix":"10.3390","volume":"18","author":[{"given":"Hyeyoung","family":"Shin","sequence":"first","affiliation":[{"name":"Department of Biomedical Science, CHA University, Seongnam 13488, Gyeonggi, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3317-0961","authenticated-orcid":false,"given":"Juwon","family":"Youn","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, CHA University, Seongnam 13488, Gyeonggi, Republic of Korea"},{"name":"College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1366-3677","authenticated-orcid":false,"given":"Chang Kyu","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seungwoon","family":"Baik","sequence":"additional","affiliation":[{"name":"ORANDBIO Co., Ltd., Uiwang 16108, Gyeonggi, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae-Keun","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, CHA University, CHA Bundang Medical Center, Seongnam 13496, Gyeonggi, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4641-7883","authenticated-orcid":false,"given":"Dong Keun","family":"Han","sequence":"additional","affiliation":[{"name":"ORANDBIO Co., Ltd., Uiwang 16108, Gyeonggi, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20417314241280359","DOI":"10.1177\/20417314241280359","article-title":"Discovery of bioactive peptides as therapeutic agents for skin wound repair","volume":"15","author":"Shahabudin","year":"2024","journal-title":"J. Tissue Eng."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"200223","DOI":"10.1098\/rsob.200223","article-title":"Wound healing: Cellular mechanisms and pathological outcomes","volume":"10","author":"Wilkinson","year":"2020","journal-title":"Open Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"20417314241260436","DOI":"10.1177\/20417314241260436","article-title":"Delivery of dental pulp stem cells by an injectable ROS-responsive hydrogel promotes temporomandibular joint cartilage repair via enhancing anti-apoptosis and regulating microenvironment","volume":"15","author":"Ma","year":"2024","journal-title":"J. Tissue Eng."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4929","DOI":"10.7150\/thno.41839","article-title":"Bioactive antibacterial silica-based nanocomposites hydrogel scaffolds with high angiogenesis for promoting diabetic wound healing and skin repair","volume":"10","author":"Li","year":"2020","journal-title":"Theranostics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e2413373","DOI":"10.1002\/adma.202413373","article-title":"Adaptable Hydrogel with Strong Adhesion of Wet Tissue for Long-Term Protection of Periodontitis Wound","volume":"37","author":"Chen","year":"2025","journal-title":"Adv. Mater."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"20417314251342175","DOI":"10.1177\/20417314251342175","article-title":"Advances in hydrogels for capturing and neutralizing inflammatory cytokines","volume":"16","author":"Qin","year":"2025","journal-title":"J. Tissue Eng."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/s13287-023-03345-0","article-title":"Stem cell-derived exosomes: Emerging therapeutic opportunities for wound healing","volume":"14","author":"Zhou","year":"2023","journal-title":"Stem Cell Res. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1007\/s13770-025-00748-3","article-title":"Human Nasal Olfactory Stem Cell-Derived Extracellular Vesicles Improve the Repair of Rat Nerves","volume":"22","author":"Bonnet","year":"2025","journal-title":"Tissue Eng. Regen. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1186\/s13287-022-02980-3","article-title":"Human adipose-derived mesenchymal stem cells-derived exosomes encapsulated in pluronic F127 hydrogel promote wound healing and regeneration","volume":"13","author":"Zhou","year":"2022","journal-title":"Stem Cell Res. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Hade, M.D., Suire, C.N., and Suo, Z. (2021). Mesenchymal Stem Cell-Derived Exosomes: Applications in Regenerative Medicine. Cells, 10.","DOI":"10.3390\/cells10081959"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"112688","DOI":"10.1016\/j.matdes.2024.112688","article-title":"Sustained delivery of extracellular vesicles using UiO-66-NH2 crosslinked hydrogel for accelerating chronic diabetic wound-healing","volume":"238","author":"Pan","year":"2024","journal-title":"Mater. Des."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"20417314241265897","DOI":"10.1177\/20417314241265897","article-title":"Mechanisms of hydrogel-based microRNA delivery systems and its application strategies in targeting inflammatory diseases","volume":"15","author":"Hu","year":"2024","journal-title":"J. Tissue Eng."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e20230029","DOI":"10.1002\/SMMD.20230029","article-title":"Modification and crosslinking strategies for hyaluronic acid-based hydrogel biomaterials","volume":"2","author":"Luo","year":"2023","journal-title":"Smart Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s12951-024-02315-9","article-title":"Hydrogel-mediated extracellular vesicles for enhanced wound healing: The latest progress, and their prospects for 3D bioprinting","volume":"22","author":"Zheng","year":"2024","journal-title":"J. Nanobiotechnol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"113985","DOI":"10.1016\/j.jconrel.2025.113985","article-title":"MSC-derived exosomes injectable hyaluronic acid hydrogel for enhanced chronic wound healing","volume":"385","author":"Yu","year":"2025","journal-title":"J. Control. Release"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.2147\/CCID.S409310","article-title":"Post-Treatment of Micro-Needling with a Dexpanthenol-Containing Ointment Accelerates Epidermal Wound Healing in Human 3D Skin Models","volume":"16","author":"Marquardt","year":"2023","journal-title":"Clin. Cosmet. Investig. Dermatol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ghadami, S., and Dellinger, K. (2023). The lipid composition of extracellular vesicles: Applications in diagnostics and therapeutic delivery. Front. Mol. Biosci., 10.","DOI":"10.3389\/fmolb.2023.1198044"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"18718","DOI":"10.1038\/s41598-020-75561-0","article-title":"Application of peptides with an affinity for phospholipid membranes during the automated purification of extracellular vesicles","volume":"10","author":"Ishida","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wang, Y., Hofmann, L., Huber, D., Lochbaum, R., Ludwig, S., Brunner, C., Hoffmann, T.K., Lehner, R., and Theodoraki, M.N. (2024). Molecular and Functional Cargo of Plasma-Derived Exosomes in Patients with Hereditary Hemorrhagic Telangiectasia. J. Clin. Med., 13.","DOI":"10.3390\/jcm13185430"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100023","DOI":"10.1016\/j.vesic.2023.100023","article-title":"Current challenges surrounding exosome treatments","volume":"2","author":"Tzng","year":"2023","journal-title":"Extracell. Vesicle"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s13287-021-02697-9","article-title":"The application of mesenchymal stromal cells (MSCs) and their derivative exosome in skin wound healing: A comprehensive review","volume":"13","author":"Bian","year":"2022","journal-title":"Stem Cell Res. Ther."},{"key":"ref_22","first-page":"224","article-title":"Matrix metalloproteinase interactions with collagen and elastin","volume":"44","year":"2015","journal-title":"Matrix Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"a041225","DOI":"10.1101\/cshperspect.a041225","article-title":"Angiogenesis in Wound Repair: Too Much of a Good Thing?","volume":"14","author":"Han","year":"2022","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4361","DOI":"10.1038\/s41467-024-48719-x","article-title":"Controlled oxygen delivery to power tissue regeneration","volume":"15","author":"Zoneff","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5753","DOI":"10.1039\/D4BM00673A","article-title":"Exosomes derived from mucoperiosteum Krt14(+)Ctsk(+) cells promote bone regeneration by coupling enhanced osteogenesis and angiogenesis","volume":"12","author":"Zhou","year":"2024","journal-title":"Biomater. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"144174","DOI":"10.1016\/j.cej.2023.144174","article-title":"Continuous NO dual-generation by ZnO nanoparticle conjugated with \u03b1-lipoic acid for functional biodegradable vascular stent","volume":"470","author":"Baek","year":"2023","journal-title":"Chem. Eng. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3458","DOI":"10.1039\/D4BM00355A","article-title":"Chitosan-based multifunctional oxygenating antibiotic hydrogel dressings for managing chronic infection in diabetic wounds","volume":"12","author":"Abri","year":"2024","journal-title":"Biomater. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"0139","DOI":"10.34133\/bmr.0139","article-title":"Food-Derived Tripeptide-Copper Self-Healing Hydrogel for Infected Wound Healing","volume":"29","author":"Chen","year":"2025","journal-title":"Biomater. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"0105","DOI":"10.34133\/bmr.0105","article-title":"Hollow Bismuth Nanoparticle-Loaded Gelatin Hydrogel Regulates M2 Polarization of Macrophages to Promote Infected Wound Healing","volume":"28","author":"Lv","year":"2024","journal-title":"Biomater. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"135931","DOI":"10.1016\/j.ijbiomac.2024.135931","article-title":"Polyphenol-hyaluronic acid-based hydrogel remodels the wound microenvironment and eliminates bacterial infection for accelerating wound healing","volume":"280","author":"Liu","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.semcdb.2019.10.002","article-title":"Through the lens of hair follicle neogenesis, a new focus on mechanisms of skin regeneration after wounding","volume":"100","author":"Wier","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1152\/physrev.00067.2017","article-title":"Wound Healing: A Cellular Perspective","volume":"99","author":"Rodrigues","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1046\/j.1523-1747.2003.12019.x","article-title":"Severely impaired wound healing in the collagenase-resistant mouse","volume":"120","author":"Beare","year":"2003","journal-title":"J. Investig. Dermatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1038\/s41598-022-04856-1","article-title":"Regeneration of collagen fibrils at the papillary dermis by reconstructing basement membrane at the dermal-epidermal junction","volume":"12","author":"Iriyama","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3363","DOI":"10.1038\/s41467-021-23448-7","article-title":"A small molecule HIF-1\u03b1 stabilizer that accelerates diabetic wound healing","volume":"12","author":"Li","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.jjcc.2022.09.002","article-title":"The roles of HIF-1\u03b1 signaling in cardiovascular diseases","volume":"81","author":"Sato","year":"2023","journal-title":"J. Cardiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1007\/s13770-024-00667-9","article-title":"Collagen-Heparin-FGF2-VEGF Scaffolds Induce a Regenerative Gene Expression Profile in a Fetal Sheep Wound Model","volume":"21","author":"Gansevoort","year":"2024","journal-title":"Tissue Eng. Regen. Med."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/1003\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T04:18:53Z","timestamp":1786767533000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/1003"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["pharmaceutics18081003"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18081003","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]}}}