Emitting/Sensitizing Ions Spatially Separated Lanthanide Nanocrystals for Visualizing Tumors Simultaneously through Up‐ and Down‐Conversion Near‐Infrared II Luminescence In Vivo

Near‐infrared lights have received increasing attention regarding imaging applications owing to their large tissue penetration depth, high spatial resolution, and outstanding signal‐to‐noise ratio, particularly those falling in the second near‐infrared window (NIR II) of biological tissues. Rare earth nanoparticles containing Er3+ ions are promising candidates to show up‐conversion luminescence in the first near‐infrared window (NIR I) and down‐conversion luminescence in NIR II as well. However, synthesizing particles with small size and high NIR II luminescence quantum yield (QY) remains challenging. Er3+ ions are herein innovatively combined with Yb3+ ions in a NaErF4@NaYbF4 core/shell manner instead of being codoped into NaLnF4 matrices, to maximize the concentration of Er3+ in the emitting core. After further surface coating, NaErF4@NaYbF4@NaYF4 core/shell/shell particles are obtained. Spectroscopy studies are carried out to show the synergistic impacts of the intermediate NaYbF4 layer and the outer NaYF4 shell. Finally, NaErF4@NaYbF4@NaYF4 nanoparticles of 30 nm with NIR II luminescence QY up to 18.7% at room temperature are obtained. After covalently attaching folic acid on the particle surface, tumor‐specific nanoprobes are obtained for simultaneously visualizing both subcutaneous and intraperitoneal tumor xenografts in vivo. The ultrahigh QY of down‐conversion emission also allows for visualization of the biodistribution of folate receptors. NIR II luminescent nanoparticles with Er3+‐rich core and Yb3+‐rich shell are prepared. The spatial separation of emitters and sensitizers leads to strong NIR II luminescence. Through surface folic acid conjugation, a tumor specific probe is obtained, which perfectly integrates the advantages of up‐ and down‐conversion luminescence for achieving sensitive tumor imaging, particularly for showing the heterogeneous expression of pathological indicators in vivo.