Dual photosensitizers modified up-conversion nanoparticles for enhanced photodynamic therapy with single NIR irradiation

Photodynamic therapy (PDT) is a promising non-invasive anticancer approach that relies on photosensitizers (PSs) activated by specific light wavelengths to generate cytotoxic reactive oxygen species, particularly singlet oxygen (¹O₂), selectively destroying tumor cells. However, conventional PDT faces challenges due to the poor bioavailability of hydrophobic PSs and the limited tissue penetration of UV/visible light, hindering its efficacy for deep-seated or large tumors. To address these limitations, we developed a novel nanoplatform integrating up-conversion nanoparticles (UCNPs) with dual photosensitizers-5-aminolevulinic acid and Rose Bengal-encapsulated in a mesoporous silica-folic acid (FA) coating. Upon 980 nm near-infrared (NIR) irradiation, the UCNPs emit two kinds visible light, simultaneously activating both PSs to enhance ¹O₂ production, thereby inducing synergistic apoptosis and autophagy in cancer cells. Furthermore, cyanine 5 (CY5)-modified UCNPs enable imaging-guided tumor targeting via FA receptor-mediated uptake. In vitro and in vivo studies demonstrate significantly improved PDT efficacy with the dual-PSs system compared to single-PS modalities. This strategy offers a potent solution for deep-tumor PDT, showcasing substantial potential for clinical translation.