Dog-bone shaped gold nanoparticle-mediated chemo-photothermal therapy impairs the powerhouse to trigger apoptosis in cancer cells

The mitochondrion has emerged as one of the uncommon targets in cancer therapeutics due to its involvement in cancer generation and progression. Consequently, nanoplatform mediated delivery of anti-cancer drugs into the mitochondria of cancer tissues demonstrated immense potential in cancer treatment. In the last couple of decades, gold nanoparticles have gained incredible attention in biomedical applications due to their easy synthesis, size-shape tenability, optical properties and outstanding photothermal ability. However, application of gold nanoparticles to target mitochondria to induce the chemo-photothermal effect in cancer has remained in its infancy. To address this, herein we have engineered dog-bone shaped gold nanoparticles (Mito-AuDB-NPs) comprising cisplatin and 10-hydroxycamptothecin as chemotherapeutic drugs along with the triphenylphosphonium (TPP) cation for mitochondria homing. Mito-AuDB-NPs exhibited a remarkable increase in temperature till 56 °C upon 18 min irradiation with 740 nm NIR LED light with a power density of 0.9 W cm⁻². These Mito-AuDB-NPs successfully homed into the mitochondria of HeLa cervical cancer cells within 1 h and induced mitochondrial outer membrane permeabilization (MOMP) under the chemo-photothermal effect leading to the generation of reactive oxygen species (ROS). This Mito-AuDB-NP-mediated mitochondrial damage triggered programmed cell death (apoptosis) by decreasing the expression of anti-apoptotic Bcl-2/Bcl-xl and increasing the expression of pro-apoptotic BAX followed by caspase-3 cleavage towards extraordinary HeLa cell killing in a synergistic manner without showing toxicity towards non-cancerous RPE-1 human epithelial retinal pigment cells. We anticipate that this dog-bone shaped gold nanoparticle-mediated chemo-photothermal impairment of mitochondria in the cancer cells can open a new direction towards organelle targeted cancer therapy.