Precision Multimodal Nanodynamic Therapy for Lung Cancer: From Tumor Microenvironment-Responsive Platforms to...

Lung cancer remains one of the most prevalent and lethal malignancies worldwide and is characterized by a complex tumor microenvironment (TME), including severe hypoxia, acidosis, elevated glutathione levels, and pronounced immunosuppression. These pathological conditions compromise the efficacy of conventional therapies and contribute to drug resistance, tumor recurrence, and metastasis. Nanodynamic therapy (NDT) is an emerging therapeutic paradigm that employs nanomaterials to amplify reactive oxygen species (ROS) generation in response to endogenous or exogenous stimuli, thereby enabling localized tumor ablation and immune reprogramming. This review systematically summarizes the biological basis of NDT in lung cancer. Particular emphasis is placed on the sequential biological processes of TME responsiveness, programmed cell death (PCD) pathway reprogramming, and immune remodeling. We comprehensively review the therapeutic applications and translational potential of four major NDT modalities-sonodynamic therapy (SDT), chemodynamic therapy (CDT), photodynamic therapy (PDT), and radiodynamic therapy (RDT)-in lung cancer. We further highlight recent advances in the integration of these modalities with lung cancer-specific therapeutic strategies. These advances include immunogenic cell death (ICD)-mediated conversion of immunologically "cold" tumors into "hot" tumors, as well as synergistic strategies incorporating EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, anti-angiogenic treatment, and inhalable pulmonary delivery systems. Finally, we critically examine major barriers to the clinical translation of NDT, including the limited availability of clinically relevant in situ models, inadequate material consistency, insufficient long-term pulmonary toxicity data, and the lack of standardized physical activation parameters. We further propose priorities for future research and clinical translation. Collectively, this review provides a systematic and integrative framework for lung cancer NDT, spanning mechanistic design, therapeutic optimization, and potential clinical translation.