Yolk–shell mesoporous silica nanoparticles (YMSNs) were synthesized via a facile approach. The YMSNs displayed a relatively uniform size, good dispersity and hemocompatibility. The YMSNs were further used to construct a redox-responsive drug delivery system for targeted tumor therapy, by employing a special rotaxane nanovalve based on Pd as an end-capping agent, disulfide bonds as intermediate linkers and folic acid as a targeting motif. Various characterizations proved that the system had been successfully constructed. A series of biological assays demonstrated that the fabricated YMSN system could be triggered by intracellular glutathione for delivering the anticancer drug doxorubicin hydrochloride (DOX), leading to cell apoptosis in vitro. More importantly, the YMSN system displayed great potential for targeted tumor therapy in vivo, with minimal toxic side effects.