Synergistic chemo-photothermal therapy using doxorubicin-loaded gold nanorods for enhanced apoptosis in lung cancer cells

Lung cancer remains one of the most lethal malignancies worldwide, largely due to late-stage detection, rapid progression, and resistance to conventional therapies. Although current modalities-surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy-have improved outcomes, long-term survival rates remain unsatisfactory. Photothermal therapy (PTT), which employs near-infrared (NIR) light to induce localized hyperthermia, has recently emerged as a promising complement to standard treatments by enhancing drug delivery and overcoming resistance. In this work, we investigated a combinatorial strategy using doxorubicin (DOX)-loaded gold nanorods functionalized with thiolated β-cyclodextrin (AuNRs@S-β-CD-DOX) in conjunction with 808 nm NIR laser irradiation in A549 human lung cancer cells. Apoptosis was evaluated through gene expression profiling, TUNEL assay, and Western blot analysis. Mechanistically, this triple approach activated both intrinsic (caspase-9) and extrinsic (caspase-8) apoptotic pathways, as evidenced by cleavage of procaspases and robust caspase-3 activation. Strikingly, the combined treatment (DOX 0.078 µM + AuNRs@S-β-CD + laser) induced apoptosis in nearly 60% of cells, far surpassing single or dual treatments, while operating at a DOX dose substantially below its IC50 value. The synergistic effect was attributed to enhanced intracellular DOX release mediated by AuNR photothermal heating and increased membrane permeability upon laser exposure. These findings demonstrate that AuNR-assisted chemo-photothermal therapy can overcome drug resistance and amplify apoptosis, providing a rational, targeted, and effective strategy for advancing lung cancer treatment.