Rationally Integrated Precise ER-targeted And Oxygen-compensated Photodynamic Immunostimulant for Immunogenicity-boosted Tumor Therapy.

Notwithstanding that immunotherapy has made eminent clinical breakthroughs, activating the immunogenicity and breaking the immunosuppressive tumor microenvironment (ITME) remains tempting yet challenging. Herein, a customized-designed immunostimulant was engineered for attenuating ITME and eliciting an immune response to address this challenge head-on. This immunostimulant was equipped with dual silica layers coated upconversion nanoparticles (UCNPs) as nanocarriers modified with N-p-Tosylglycine, in which the dense silica for chlorin e6 (Ce6) and the glutathione (GSH)-responsive degradable silica for loading resveratrol (RES) (UCNPs@SiO -Ce6@MON(RES)@ER (UCSMR )). On the one hand, UCSMR was positioned accurately in the endoplasmic reticulum (ER) guided by the ER-targeted molecular N-p-Tosylglycine. This precise ER-targeted photodynamic therapy (PDT) could generate reactive oxygen species (ROS) in situ under the 980 nm laser irradiation, which not only induced severe cell death directly but also caused intense ER stress-based immunogenic cell death (ICD) effects, triggering a tumor immune response. On the other hand, tumor hypoxia aggravated by the PDT process was effectively alleviated by RES released on-demand, which reduced oxygen consumption by impairing the mitochondrial electron transport chain (ETC). This integrated precise ER-targeted and oxygen-compensated strategy maximized the PDT effect and potentiated ICD-associated immunotherapy, which availed to attenuate ITME, activate tumor immunogenicity and further magnify anti-tumor effect. This innovative concept about PDT and immunotherapy sheds light on the cancer-related clinical application. This article is protected by copyright. All rights reserved.