Cascade-Responsive Upconversion Nanoplatform for Efficient Cell Nucleus Targeting and Boosted Photodynamic Tumor Therapy

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