Inhalable Mucoadhesive Redox‐Triggered Nanotherapeutics for p53‐Mediated Lung Cancer Therapy and Metastasis Suppression

Lung cancer remains a leading cause of cancer-related mortality worldwide, with metastatic disease accounting for ∼90% of deaths. 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-responsive thiolated chitosan nanoparticles (TCS NPs) as the first inhalable nanotherapeutic platform for tumor-selective 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-loaded TCS NPs demonstrated exceptional cancer selectivity, exhibiting significant cytotoxicity against lung cancer cells while maintaining biocompatibility with normal tissues. Treatment restored p53-mediated pathways, upregulating metastasis suppressors (KLF6 and E-cadherin) and apoptotic factors (Bax and cleaved caspase-3), 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-selective targeting.