Synergistic Chemo-Photothermal Therapy Using Doxorubicin-Loaded Gold Nanorods for Enhanced Apoptosis in Lung Cancer Cells

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, primarily due to late diagnosis, aggressive progression, and the emergence of therapeutic resistance. Although significant advances have been made in surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, long-term survival remains limited. Photothermal therapy (PTT), a minimally invasive strategy that utilizes near-infrared (NIR) light to generate localized hyperthermia, has emerged as a promising approach to overcome drug resistance and enhance therapeutic outcomes. In this study, we evaluated a combined therapeutic strategy involving doxorubicin (DOX)-loaded gold nanorods (AuNRs) functionalized with thiolated β-cyclodextrin (AuNRs@S-β-CD-DOX) and NIR laser irradiation (808 nm) in A549 human lung cancer cells. Apoptosis was assessed using gene expression analysis, TUNEL assay, and Western blotting. Mechanistically, this triple therapy activates both intrinsic (caspase-9) and extrinsic (caspase-8) apoptotic pathways, which revealed cleavage of procaspases into active forms (e.g., caspase-3 fragments at 17/19 kDa). Our results demonstrated that the triple combination (DOX 0.078 µM + AuNRs@S-β-CD + laser) significantly enhanced apoptosis—up to 60%—while enabling the use of a DOX concentration far below its IC50 level. This synergistic effect was attributed to improved intracellular delivery of DOX facilitated by AuNRs@S-β-CD-mediated photothermal release and increased membrane permeability induced by laser irradiation. These findings support the potential of chemo-photothermal therapy as a highly effective and targeted strategy against lung cancer.