Photoswitchable upconversion nanoparticles with excitation-dependent emission for programmed stepwise NIR phototherapy

Programmable control over therapeutic processes in phototherapy, like photodynamic therapy (PDT), is promising but challenging. This study uses an energy segmentation-based strategy to synthesize core-multi-shell upconversion nanoparticles (UCNPs), which can release three different colors (red, green, and blue) upon exposure to different near-infrared light (1550 nm, 808 nm, and 980 nm). By combining these UCNPs with photosensitizers and nitric oxide (NO) donors, a smart “off-on” PDT nanoplatform is developed. UCNPs enable independent activation of imaging, release of NO, and generation of reactive oxygen species using specific light wavelengths. The results show that sequential NO release before PDT can greatly alleviate tumor hypoxia by reducing oxygen consumption. This stepwise approach shows potential for precise NIR light-activated and imaging-guided phototherapy.