Endoplasmic Reticulum-Targeting NIR Cyanine ER800 Nanoparticles Promote Pyroptosis in Triple-Negative Breast Cancer.

Pyroptosis, an inflammatory form of cell death, has recently attracted increasing attention in anticancer therapy. Endoplasmic reticulum (ER)-targeted pyroptosis has emerged as a highly promising strategy in theranostics, integrating tumor imaging and therapeutic interventions. Research on the use of ER-targeted theranostic agents for triggering pyroptosis is lacking. This study aims to develop an ER-targeting theranostic agent that enables the integration of tumor imaging and cancer-targeted therapeutics. The ER-targeting NIR fluorescent cyanine ER800 was synthesized, and ER800-FA-NPs were constructed. Flow cytometry, immunofluorescence, and Western blotting were employed to assess the ER targeting effect and pyroptosis in triple-negative breast cancer (TNBC) cells in vitro. A TNBC cell xenograft model was used to investigate the antitumor efficacy. ER800-FA-NPs preferentially accumulate in the ER of TNBC cells, subsequently promoting ER stress via the generation of ROS. High ER stress triggers the activation of the GRP78-mediated PERK-eIF2α-ATF4-CHOP, ATF6, and IRE1-XBP1 signaling pathways, leading to LDH, IL-1β, and IL-18 release and cleavage of caspase-3/GSDME and ultimately promoting pyroptosis. In vivo experiments revealed that ER800-FA-NPs exhibited excellent tumor-targeting ability and antitumor efficacy against TNBC through caspase-3/GSDME pathway-mediated pyroptosis. Our research findings indicate that ER800-FA-NPs may serve as theranostic agents in tumor imaging-guided therapy, further supporting the use of ER-targeted pyroptosis for the treatment of TNBC.