The model system Pd/TiO2 (110) was used to evaluate the correlation between metal encapsulation and electronic structure of TiO2 crystals. We observed encapsulation of Pd clusters supported on TiO2 crystals, which were heavily Ar+ sputtered, Nb-doped, or reduced by vacuum annealing. In contrast, encapsulation was not observed on unreduced, undoped, or slightly sputtered TiO2 crystals. Our results indicate a strong dependence of the encapsulation process on the electron density in the conduction band of TiO2 and on the space charge formed at Pd/TiO2 interfaces. This behavior is controlled by the initial position of the Fermi energy level (E-F) of the metal and the oxide before contact is established. We proved that encapsulation reactions are favored by n-type doping of the oxide and a large work function of the metal. On the basis of this mechanism, we conclude on general trends controlling encapsulation reactions of oxide-supported metal clusters and the strong metal-support interaction (SMSI).