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While p53 gene therapy offers promise for restoring tumor suppressor function, its clinical translation has been hindered by inefficient delivery systems and pulmonary administration challenges. Here, we developed redox\u2010responsive thiolated chitosan nanoparticles (TCS NPs) as the first inhalable nanotherapeutic platform for tumor\u2010selective p53 gene delivery to treat metastatic lung cancer. Our system exploits elevated glutathione levels in cancer cells to trigger selective gene release, while mucoadhesive properties ensure prolonged pulmonary retention. The p53 DNA\u2010loaded TCS NPs demonstrated exceptional cancer selectivity, exhibiting significant cytotoxicity against lung cancer cells while maintaining biocompatibility with normal tissues. Treatment restored p53\u2010mediated pathways, upregulating metastasis suppressors (KLF6 and E\u2010cadherin) and apoptotic factors (Bax and cleaved caspase\u20103), thereby inhibiting migration, invasion, and metastatic progression. In vivo studies using ectopic xenograft and experimental metastasis models confirmed robust therapeutic efficacy, with inhaled TCS@p53 NPs achieving significant tumor suppression and reduced metastatic nodule formation while maintaining excellent safety profiles. This work presents a transformative inhalable gene therapy platform that overcomes traditional delivery limitations through tumor\u2010selective targeting.<\/jats:p>","DOI":"10.1002\/adhm.71476","type":"journal-article","created":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T04:03:51Z","timestamp":1784952231000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhalable Mucoadhesive Redox\u2010Triggered Nanotherapeutics for p53\u2010Mediated Lung Cancer Therapy and Metastasis Suppression"],"prefix":"10.1002","volume":"15","author":[{"given":"Yun Seop","family":"Shim","sequence":"first","affiliation":[{"name":"Department of Biomedical Convergence Science and Technology Advanced Institute of Science and Technology Kyungpook National University  Daegu Republic of Korea"},{"name":"Department of Intelligent Precision Healthcare Convergence Sungkyunkwan University Suwon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Min","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Biomedical Convergence Science and Technology Advanced Institute of Science and Technology Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun Kee","family":"Jo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Convergence Science and Technology Advanced Institute of Science and Technology Kyungpook National University  Daegu Republic of Korea"},{"name":"Department of Advanced Bioconvergence Kyungpook National University  Daegu Republic of Korea"},{"name":"Cell and Matrix Research Institute Kyungpook National University  Daegu Republic of 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