Endoplasmic reticulum-targeted gold nanorod for chemo-photothermal therapy induces ER stress-mediated autophagy and apoptosis in cancer cells.

Organelle-targeted nanomedicine offers new opportunities for improving cancer therapy. The endoplasmic reticulum (ER), a central regulator of protein folding and cellular stress signaling, has emerged as a promising intracellular target for inducing ER stress-mediated cancer cell death. Here, we report an ER-targeted gold nanorod platform (ER-Au-NR) engineered with cisplatin and indomethacin as chemotherapeutic agents and a dansyl-sulfonamide moiety for ER-specific targeting and subcellular imaging. The ER-Au-NR exhibits excellent photothermal performance, reaching temperatures up to 52 °C with high photostability under 808 nm near-infrared laser irradiation (0.8 W cm-2). The nanorods rapidly localize within the ER of HCT-116 colon cancer cells and induce ER stress, as evidenced by the upregulation of CHOP, IRE-1α, PERK, Cas-12, and GRP94, along with enhanced reactive oxygen species generation upon light irradiation. This ER-targeted chemo-photothermal therapy triggers autophagy (increased Beclin-1 and LC3-II/LC3-I ratio) followed by apoptosis through downregulation of Bcl-2 and COX-2 and cleavage of caspase-3 and PARP with increased BAX expression. Importantly, ER-Au-NR effectively kills HCT-116, HeLa, and MDA-MB-231 cancer cells while showing negligible toxicity toward non-cancerous RPE-1 cells. These findings highlight ER-targeted gold nanorods as a promising platform for organelle-specific chemo-photothermal cancer therapy.