Smart drug delivery nanosystems with integrated real-time monitoring capability have attracted great attention in recent years; however, they are still in a nascent stage due to a lack of proper imaging modalities. Herein, we present a novel pH-responsive drug delivery nanosystem in which a coordination complex of tannic acid and Cu2+ ions was successfully functionalized onto the surface of mesoporous silica-coated upconversion nanoparticles (UCNPs) to block premature release of the anti-cancer drug doxorubicin (DOX) from the mesopores of the particles. In addition, loading of the drug enables luminescence resonance energy transfer (LRET) from the UCNPs to DOX, which results in quenching of the emission of the UCNPs. The metal-phenolic networks are degraded in the acidic environment in living cells, leading to DOX release from the mesopores and thus to elimination of LRET. Therefore, the changes in upconversion luminescence enable monitoring of the pH-triggered drug release in real-time. This strategy will facilitate the design of smart drug delivery systems and theranostics.