Dual-Targeted Codelivery of XBP1 Inhibitor and Photosensitizer by GSH-Responsive Functional Silica Nanoparticles for...

Immunogenic cell death (ICD) plays a critical role in regulating the immunogenicity of cancer cells to activate the immune response, thus influencing the control of tumor growth. The continuous accumulation of ROS and activation of the endoplasmic reticulum stress (ERS) pathway are both vital for the amplification of ICD effects. Inhibition of the IRE1α-XBP1 signal is considered to facilitate the reduction of the adaptive response of the ER, which exacerbates ERS. Herein, a multifunctional nanoparticle (FE/IR780-NP) composed of XBP1 inhibitor-loaded mesoporous nanoparticles coated with photosensitizer-β-cyclodextrin complexes via GSH-responsive linkers was constructed and characterized. The results of in vitro cellular assays indicate that under intracellular conditions, after the shearing of GSH, the FE/IR780-NPs are divided into peptide-modified Toy-loaded mesoporous silica nanoparticles targeting the ER and IR780-β-cyclodextrin complexes targeting the mitochondrion. The combination of NIR irradiation and XBP1 inhibition significantly potentiates ER stress and amplifies the effects of ICD. Enhanced calreticulin (CRT) exposure, the main indicator of ICD effects, was almost double that of the groups without NIR irradiation (approximately 4 times higher than that of the single toy-treated groups). By establishing a 4T1 triple-negative breast cancer model in mice, the enhanced suppression of tumor growth by FE/IR780-NP-mediated photoimmunotherapy was also supported by in vivo results. FE/IR780-NPs can serve as promising candidates for the amplification of ICD effects to control the progression of aggressive cancers.