Plasmonic photothermal therapy (PPTT) employing plasmonic gold nanorods (GNRs) presents a potent strategy for eradication of tumors including aggressive brain gliomas. Despite its promise, there is a pressing need for a more comprehensive evaluation of PPTT using sophisticated in vitro models that closely resemble tumor tissues, thereby facilitating the elucidation of therapeutic mechanisms. In this study, we exposed 3D glioma spheroids (tumoroids) to (16-mercaptohexadecyl)trimethylammonium bromide-functionalized gold nanorods (MTAB-GNRs) and a near-infrared (NIR) laser. We demonstrate that the photothermal effect can be fine-tuned by adjusting the nanoparticle concentration and laser power. Depending on the selected parameters, the laser can trigger either regulated or non-regulated cell death (necrosis) in both mouse GL261 and human U-87 MG glioma cell lines, accompanied by translocation of phosphatidylserine in the membrane. Our investigation into the mechanism of regulated cell death induced by PPTT revealed an absence of markers associated with classical apoptosis pathways, such as cleaved caspase 3. Instead, we observed the presence of cleaved caspase 1, gasdermin D, and elevated levels of NLRP3 in NIR-irradiated tumoroids, indicating the activation of pyroptosis. This finding correlates with previous observations of lysosomal accumulation of MTAB-GNRs and the known lysosomal pathway of pyroptosis activation. We further confirmed the absence of toxic breakdown products of GNRs using electron microscopy, which showed no melting or fragmentation of gold nanoparticles under the conditions causing regulated cell death. In conclusion, PPTT using coated gold nanorods offers significant potential for glioma cell elimination occurring through the activation of pyroptosis rather than classical apoptosis pathways.

Department of Chemistry Faculty of Science University of Hradec Kralove Hradec Kralove Czech Republic; Biomedical Research Center University Hospital Hradec Kralove Czech Republic

Department of Physiology 2nd Faculty of Medicine Charles University Prague Czech Republic

Electron Microscopy Core Facility Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Electron Microscopy Core Facility Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic; Laboratory of Biology of the Cell Nucleus Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Genome Integrity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Genome Integrity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic; Department of Laser Physics and Photonics Faculty of Nuclear Sciences and Physical Engineering Czech Technical University Prague Prague Czech Republic

Laboratory of Genome Integrity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic; Department of Physiology 2nd Faculty of Medicine Charles University Prague Czech Republic

Laboratory of Genome Integrity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic; Genome Integrity Group Danish Cancer Institute Danish Cancer Society Copenhagen Denmark; Department of Medical Biochemistry and Biophysics Science For Life Laboratory Division of Genome Biology Karolinska Institute Stockholm Sweden

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