Cascade-Responsive\nUpconversion Nanoplatform for Efficient\nCell Nucleus Targeting and Boosted Photodynamic Tumor Therapy

In order to increase tumor tissue penetration, enhance\nphototherapy\nefficiency, and reduce off-target toxicity, we have developed a dual-locked\nupconversion nanoplatform (UCNP@Glu-DMMA) with a charge-reversal property\nfor tumor-specific, cell nucleus-penetrating photodynamic therapy\n(PDT). The negative charge on the surface of UCNP@Glu-DMMA ensured\nexcellent stability during blood circulation and accumulation in the\ntumor microenvironment (TME). Subsequently, the combined effect of\nthe acidic TME and γ-glutamyl transpeptidase (GGT) triggered\na reversal of the surface charge from negative to positive. This reversal\nenhanced the uptake efficiency of UCNP, leading to an increased intracellular\ndrug concentration, deep tumor penetration, and direct nucleus delivery\nfor the localized release of reactive oxygen species, resulting in\nrobust DNA damage. As a result, the efficacy of PDT was significantly\nand precisely boosted for GGT-overexpressed tumors. This work provides\na promising strategy to engineer therapeutic platforms for managing\na variety of diseases based on different biomarkers.