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Existing treatments\u2014including oral films, sprays, frosts, and powders\u2014often fail to be effective due to rapid dilution and clearance in the moist oral environment. This study is the first to investigate the use of Cold Atmospheric Plasma (CAP) for treating oral ulcers and its underlying molecular mechanisms. A novel high\u2010bioavailability, mucoadhesive therapy combining handheld three dimensions (3D) multi\u2010microhole CAP is developed with a nanogel\u2010based pharmaceutical system containing glucose oxidase (GOx) and catalase (CAT), termed GCN. These results showed that both CAP alone and CAP combined with GCN significantly accelerate oral ulcer healing, modulate immune responses, and activate the Epidermal Growth Factor Receptor (EGFR) in acetic acid\u2010induced oral ulcers, outperforming untreated controls and the conventional medication, Watermelon Frost (WF). Furthermore, the CAP+GCN combination enhances therapeutic effects by promoting fibroblast generation. CAP pretreatment also enhances cell permeability and nanoparticle uptake, improving tissue adhesion. These findings are validated in primary Human Gingival Fibroblasts (HGF) and Human Periodontal Ligament Stem Cells (PDLSC) from healthy donors, as well as an oral ulcer model in rats, demonstrating superior biocompatibility and safety.<\/jats:p>","DOI":"10.1002\/adhm.202403223","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T00:45:36Z","timestamp":1738629936000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Next\u2010Generation Oral Ulcer Management: Integrating Cold Atmospheric Plasma (CAP) with Nanogel\u2010Based Pharmaceuticals for Inflammation Regulation"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3076-9614","authenticated-orcid":false,"given":"Yanfen","family":"Zheng","sequence":"first","affiliation":[{"name":"Xiamen Key Laboratory of Stomatological Disease Diagnosis and Treatment Department of Pharmacy Stomatological Hospital 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