Decoding shape- and type-dependent cellular toxicity of plasmonic nanoparticles in healthy and cancer cells

Plasmonic photothermal therapy (PTT) offers a promising route for selective cancer treatment through laser-activated metallic nanoparticles (NPs). Here, we systematically evaluated how NP geometry, size, and elemental composition govern photothermal toxicity responses in healthy fibroblasts (L929) and lung carcinoma cells (A549) under both laser-free and 808 nm laser-irradiated conditions. Spherical, rod-shaped, and star-shaped gold nanoparticles (AuNP, AuNR, AuNS), together with spherical and prismatic silver nanoparticles (AgNP, AgNPr), were synthesized, characterized, and assessed across multiple biological endpoints. Cellular viability (MTT), reactive oxygen species (ROS) generation, DNA damage (Comet assay), inflammatory cytokine release (TNF-α, IL-6, IL-10), and apoptosis (Annexin V/PI staining and caspase-3/9 activation) were systematically analyzed. Laser activation markedly amplified cancer-selective cytotoxicity, with AuNR and AgNPr exhibiting the strongest photothermal responses while largely sparing healthy cells. AuNR and 20 nm AuNP induced pronounced ROS generation and caspase-dependent apoptosis in A549 cells upon irradiation, whereas AgNPr preferentially promoted DNA damage and inflammatory signaling in cancer cells with minimal effects in L929 cells. Across all nanostructures, laser irradiation selectively intensified genotoxic and inflammatory responses in tumor cells, highlighting a strong dependence on nanoparticle geometry and plasmonic resonance matching. Collectively, these results demonstrate that NP shape and photothermal activation synergistically dictate therapeutic/toxic effects and selectivity. AuNR and AgNPr emerge as leading candidates for precision PTT, combining potent anticancer activity with favorable biocompatibility. This work provides mechanistic insight into structure-activity relationships in plasmonic PTT and informs the rational design of next-generation photothermal nanotherapeutics.