An efficient and facile method was designed to produce an acid–base bifunctional mesoporous silica nanoreactor (MS-SO₃H@MS@MS-NH₂) with acid sites on the inner core, unfunctionalized silica as the neutral zone shell and basic sites on the outer shell. Such acid core–neutral zone–base shell structure design resulted in excellent spatial separation of the hostile functionalities and was better than that of the core–shell structure. The spatial order of acid sites and basic sites in the mesoporous silica nanosphere offered a designated diffusion pathway that was favorable for reaction species, while the mesoporous structure endowed the material with the confinement effect. As a result, the core–shell–shell structured mesoporous silica nanosphere was an excellent bifunctional catalyst for one-pot cascade reaction sequences.