Herein we report an inside-out preinstallation-infusion-hydration method for targeted synthesis of Keggin heteropoly acids (silicomolybdic acid, H(4)SiMo(12)O(40)) within mesoporous silica (SiO(2)) hollow spheres. In this process, discrete molybdenum dioxide (MoO(2)) nanoparticles with diameter size ranging from 25 to 60 nm were first prepared by a one-pot hydrothermal route in water/ethanol mixed solvents at 180 °C, which were then used as cores to grow the shell of supramolecular templated silica with tetraethyl orthosilicate (TEOS) and hexadecyltrimethyl- ammonium chloride (CTACl) in alkaline solution. By thermal treatment of as-synthesized MoO(2)@SiO(2) core-shell spheres, the organic template was burned off and mesoporous shell was formed (BET specific surface area was as high as 872 m(2)/g). Meanwhile, the encapsulated MoO(2) was oxidized to Mo(6+) and infused to the mesoporous silica shells, forming heptamolybdate species (Mo(7)O(24)(6-)) uniformly dispersed on the mesopore surfaces of silica, while generating void space at the center of spheres. After hydration with water, H(4)SiMo(12)O(40) was formed by reaction between the surface Mo(7)O(24)(6-) and silica species in the presence of water. The prepared H(4)SiMo(12)O(40) @mSiO(2) hollow spheres were tested for Friedel-Crafts alkylation of toluene by benzyl alcohol. The H(4)SiMo(12)O(40)@mSiO(2) catalysts fabricated via this novel route exhibited excellent catalytic activity toward benzylation of toluene, which was approximately 2.6 times as high as that of commercial Amberlyst-15 catalyst. In addition, the H(4)SiMo(12)O(40)@mSiO(2) catalyst was very robust and could be reused after regeneration.