Rationally designed upconversion nanoparticles for NIR light-controlled lysosomal escape and nucleus-based photodynamic therapy

Cell nucleus-based photodynamic therapy is a highly effective method for cancer therapy, but it is still challenging to design nucleus-targeting photosensitizers. Here, we propose the "one treatment, multiple irradiations" strategy to achieve nucleus-based photodynamic therapy using the photosensitizer rose bengal (RB)-loaded and mesoporous silica-coated upconversion nanoparticles with the surface modification of amine group (UCNP/RB@mSiO₂-NH₂ NPs). After implementation into cancer cells, the rationally designed UCNP/RB@mSiO₂-NH₂ NPs could be specifically accumulated in the acidic lysosomes due to their amino group-decorated surface. Upon a short-term (3 min) irradiation of 980 nm near-infrared light, the reactive oxygen species produced by RB through the Förster resonance energy transfer between the upconversion nanoparticles and RB molecules could effectively destroy lysosomes, followed by the release of the UCNP/RB@mSiO₂-NH₂ NPs from the lysosomes. Subsequently, these released UCNP/RB@mSiO₂-NH₂ NPs could be transferred into the cell nucleus, where a second 980 nm light irradiation was conducted to achieve the nucleus-based photodynamic therapy. The rationally designed UCNP/RB@mSiO₂-NH₂ NPs showed excellent anticancer performance in both two-dimensional and three-dimensional cell models using the "one treatment, multiple irradiations" strategy.