The development of drug delivery vehicles without side effects to normal physiological tissues represents an urgent challenge for safety and effective nanomedicine. Herein, a multifunctional drug delivery vehicle with ultralow leakage was presented, containing an ordered mesoporous resin as a polymer core and homogeneous Fe nanodots-doped silica as the biodegradable shell. In this core-shell structure, the Fe-doped silica shell acts as a compact inorganic cap to seal doxorubicin into the mesoporous polymer cores, but also serves as a superparamagnetic agent for magnetic targeting and magnetic resonance imaging (MRI). Importantly, the caps can be opened via Fe extraction-induced degradation to slowly release the loaded drug under the acidic tumor environment, while achieving ultralow drug leakage under normal in vivo blood circulation (physiological environment). This unique core-shell nanospheres with ultralow drug leakage were demonstrated to achieve side effects-avoided targeting chemotherapy guided by MRI with improved therapeutic outcomes, which showing great potential for efficient cancer theranostics.