Metal-organic frameworks (MOFs) have spurred tremendous research interest in the fields of nanoscience and nanotechnology. However, exploring their biomedical applications is still a daunting challenge. In this work, we employed an acid-degradable MOF, zeolitic imidazolate framework-8 (ZIF-8), both as a self-sacrificial template to synthesize uniform size/morphology-controllable hollow mesoporous silica materials (HMSNs) and as a mesopore blocker for fabricating a pH-responsive HMSN-based drug delivery system. Starting from the ZIF-8 template, a layer of mesoporous silica is coated on ZIF-8 and subsequently the template was self-degraded under acidic conditions to obtain HMSNs. A series of monodisperse HMSNs ranging from ca. 80 nm to ca. 3000 nm with morphologies that give rare examples of cubic and dodecahedral morphologies has been prepared. It is demonstrated that the as-made HMSNs possess well-defined mesopores, huge cavities and good biocompatibility, which make them favourable for drug delivery. So, ZIF-8 was then grafted onto the HMSN to block the pore orifice for pH-responsive intracellular anticancer drug release. The results indicated that the ZIF-8-coated HMSN with encapsulated doxorubicin hydrochloride (DOX) was an efficient drug delivery vehicle in cancer therapy using pH-responsive release. This strategy sheds new light on the application of MOF materials and provides great potential for biomedical applications.