Metal Nanoparticles as Sensitizers in Energy-Based Therapies for Lung Cancer: From Mechanistic Insights to Clinical Translation.

Lung cancer remains a leading cause of cancer-related morbidity and mortality worldwide. Energy-based modalities, including radiotherapy, photodynamic therapy, and radiofrequency ablation, are now integral to multidisciplinary treatment regimens for this disease. However, the clinical efficacy of these approaches is severely constrained by intrinsic tumor hypoxia, the robust DNA repair machinery of cancer cells, and the off-target toxicity inflicted upon adjacent normal tissues. To address these bottlenecks, research has demonstrated that metallic nanoparticles (MNPs), by virtue of their unique physicochemical properties, can effectively enhance radiation energy deposition, modulate the tumor microenvironment, and achieve targeted delivery, thereby emerging as highly promising sensitizers for energy-based therapies. For instance, gold nanoparticles (AuNPs) can achieve a radiation sensitization enhancement factor ranging from 1.2 to over 2.0 in vitro by increasing local dose deposition and generating secondary electrons, an effect that is dependent on nanoparticle size and concentration. Notably, this strategy has progressed to clinical validation, with silica-based gadolinium nanoparticles (AGuIX) being particularly prominent; these have completed Phase I/II clinical trials for the treatment of various malignancies, including lung cancer and brain metastases, confirming the translational potential of this technology. Here, we systematically review the advances in the application of MNPs in energy-based therapies for lung cancer and provide an in-depth analysis of their multimodal sensitization mechanisms, including the generation of ROS, sensitization of DNA damage, and induction of immunogenic cell death. On this basis, we further summarize the key translational barriers currently faced. Namely, we identify the in vivo safety of nanoparticles, the lack of standardized evaluation systems, and bottlenecks in large-scale production as key barriers, and we offer an outlook on future directions that integrate smart responsive nanosensitizers with clinical personalized therapy.