A seeded watermelon-like mesoporous nanostructure (mSiO2@CdTe@SiO2, mSQS) composed of a novel dendritic mesoporous silica core, fluorescent CdTe quantum dots (QDs), and a protective solid silica shell is successfully fabricated by loading QDs into dendritic mesoporous silica nanoparticles through electrostatic interaction, and then coating with a solid silica shell by the modified Stöber method. The shell thickness of mSQS can be tuned from 0 to 32 nm as desired by controlling the reaction parameters, including the amount of silica precursor, tetraethyl orthosilicate, that is introduced, the solvent ratio (H2O:ethanol), and the amount of catalyst (NH3H2O). These fluorescent mSiO2@QDs@SiO2 nanoparticles possess excellent stability and thickness-dependent cytotoxicity, and are successfully applied to bioimaging. A seeded watermelon-like fluorescent mesoporous nanostructure (mSiO2@CdTe@SiO2) composed of a novel dendritic mesoporous silica core, fluorescent CdTe quantum dots, and a protective solid silica shell is successfully fabricated and applied to in vitro and in vivo bioimaging.