Developing multifunctional drug delivery systems for achieving the combination of diagnosis and treatment is highly desirable due to the improved therapeutic effect and minimized side effects. Metal-organic frameworks (MOFs) as emerging porous materials exhibit many intriguing properties for application in biomedicine. Here, MOFs coated up-conversion nanoparticles (UCNPs) were synthesized by a facile one-pot liquid-solid-solution (LSS) method for the first time. The encapsulation of UCNPs into MIL-100(Fe) shell leads to core-shell structured UCNPs@MIL-100(Fe) NPs. Upon 808 nm laser irradiation, the sample produces abundant reactive oxygen species (ROS) of hydroxyl radical ((OH)-O-center dot) in the presence of H2O2 derived from Fenton reaction, which are highly toxic to tumor cells. Meanwhile, the MIL-100(Fe) shell efficiently converts the excited laser energy into heat, thus achieving apparent photothermal therapy (PTT) effect. Furthermore, the porous structure and high specific area of the MOFs shell make it possible to load large amount of toxic doxorubicin (DOX). In vivo and in vitro results indicate that DOX loaded UCNPs@MIL-100(Fe) NPs markedly suppress the tumor cell growth under very mild 808 nm laser irradiation (0.5 W/cm(2)) based on synergistic (photodynamic, photothermal, and chemo-therapy) effect. This study presents a feasible strategy for developing multifunctional drug delivery system based on MOFs that are responsive to high-penetrated 808 nm laser.