Lanthanide-doped upconversion nanoparticles (UCNPs) are a promising new gen- eration of imaging agents for bioimaging due to no auto-fluorescence, large penetration depth and non-blinking. In this paper an efficient ultra-small core-shell UCNP was synthesized using a hydrothermal method and a thermal decomposition procedure. A new inorganic host — ZrO2 was used for its low phonon energy and high absorption coefficient [1]. The as-synthesized core- shell nanoparticles has a diameter smaller than 5 nm. An aptamer was employed as a recognizer for protein recognition to implement the bioimaging. Therefore, the small and efficient core-shell nanoparticles was fabricated to achieve the single-proteins-targeted imaging.