An inclusion complex of NaYF4 :Yb(3+) ,Er(3+) upconversion nanoparticles with α-cyclodextrin in aqueous conditions exhibits luminescence quenching when excited at 980 nm. This non-radiative relaxation leads to an unprecedented photoacoustic signal enhancement. In vivo localization of α-cyclodextrin-covered NaYF4 :Yb(3+) ,Er(3+) is demonstrated using photoacoustic tomography in live mice, showing its high capability for photoacoustic imaging.