Activatable Phototheranostic Nanoplatform for Fluorescence Turn-On Imaging and Photodynamic Immunotherapy of Liver Cancer

Abstract The phototheranostics combined diagnostic and therapeutic effects have proven to be promising for the precision medicine. However, the clinical application of phototheranostics is largely limited by its poor targeting, “always-on” photosensitivity, and suboptimal therapeutic efficacy. To overcome these limitations, we designed an activatable phototheranostic nanoplatform with turn-on fluorescence and photodynamic immunostimulatory activity. In this study, the phototheranostic nanoplatform, termed ISSPG, integrated the photosensitizer IR780 and the anti-glypican-3 antibody via a disulfide bridge, offering favorable biosafety and stability. Following systemic administration, ISSPG preferentially accumulated in glypican 3-overexpressing Hepa1-6 tumors with improved tissue penetration. Under laser irradiation, the resultant reactive oxygen species disrupted lysosomes, preventing the degradation and elimination of ISSPG. Subsequently, the high concentration of glutathione in tumor cells cleaved the disulfide bond in ISSPG, further recovering the photoactivity of ISSPG and making it bright only in tumor sites with negligible background. Remarkably, the enhanced photodynamic activity effectively induced immunogenic cell death, thereby boosting the efficacy of photodynamic-immunotherapy and achieving robust suppression of both primary and residual tumors. This work reports a simple yet versatile strategy for enhanced photodynamic-immunotherapy and precise fluorescence imaging.