We report the design and realization of yolk–shell structured nanospheres with periodic mesoporous organosilica (PMO) nanospheres or noble metal nanoparticles encapsulated in mesoporous silica shells via a selective etching method. These architectures have well controlled structure, size and morphology. The yolk–shell structured PMO@SiO₂ nanoparticles can be precisely functionalized with different catalytic functionalities, even incompatible acidic and basic groups: the PMO core with amino (–NH₂) groups and the mesoporous silica shell with sulfonic acid (–SO₃H) groups. As a nanoreactor, the as-synthesized Au@SiO₂ nanospheres show faster reduction of 4-nitrophenol than that of nitrobenzene. Furthermore, the prepared PMO-NH₂@SiO₂-SO₃H nanoparticles can be used as bifunctional catalysts with highly efficient catalytic performance for catalyzing the deacetalization-Henry cascade reaction.