An NIR/GSH-responsive nanoplatform based on tetrasulfide bridging for targeted synergistic tumor therapy.

The efficient treatment of malignant tumors remains a major challenge in the biomedical field. To address the high toxicity and side effects of traditional chemotherapy, poor tumor targeting, and the limited effectiveness of single therapy, this study developed an intelligent nanoplatform (USMFC) that responds to both near-infrared (NIR) light and the tumor microenvironment by integrating upconversion nanoparticles (UCNPs), a tetrasulfide-bridged mesoporous silica (mSiO₂) shell, and folic acid (FA) for active tumor targeting, with polyethylene glycol (PEG) electrostatically adsorbed as the outermost layer. Under 980 nm excitation, the red emission from the UCNPs activated the photosensitizer methylene blue, enabling deep-tissue photodynamic therapy (PDT). The tetrasulfide bridges are cleaved in the high-glutathione (GSH) tumor microenvironment, triggering the controlled release of doxorubicin (DOX) (up to 82.3%), while simultaneous GSH depletion results in a 2.6-fold increase in effective ROS production and enhanced PDT efficacy. Additionally, Cu₂S nanoparticles confer excellent photothermal performance (36.2% conversion efficiency), enabling photothermal therapy (PTT) and photothermally enhanced release of the drug DOX. The modification of the outermost PEG layer further endows the nanoplatform with improved colloidal stability and biosafety. In vitro cell experiments confirmed that the nanoplatform has good biocompatibility and efficient cell uptake ability and effectively kills tumor cells through the triple synergistic effect of PDT/PTT/chemotherapy, reducing the survival rate of 4T1 cells to 18.3% at a concentration of 150 μg/mL. This study provides a new strategy for efficient and low-toxicity synergistic tumor therapy.