Here we report a novel drug delivery system using mesoporous inner-empty upconversion microspheres carrying drugs with ZnO quantum dots (UCMPS@ZnO) acting as a 'door-keeper' for pH-triggered drug release. Compared to other upconversion drug delivery systems, it is smarter, simpler, more efficient and more biocompatible. In particular, the UCMPS@ZnO microspheres show low cytotoxicity, are simple to produce and have a high drug loading rate (15%). Promisingly, a mice treatment experiment demonstrated that the multifunctional nanoparticles have efficient inhibition of tumor growth after a 14-day treatment. This makes UCMPS@DOX-ZnO microspheres a promising theranostic candidate in cancer treatment and clinical trials.