A thermoresponsive drug delivery system was constructed based on microwave radiation. Core-shell mesoporous silica nanoparticles were synthesized by using ZnO@Fe3O4 nanoparticles as the core for enhancing heat generation under microwave radiation and mesoporous silica as the shell for drug accommodation. A novel short peptide Phe-Phe-Gly-Gly (N-C) with good self-assembly performance was grafted on the surface of mesoporous silica as a nanovalve. The modified peptide on mesoporous silica nanoparticles blocked the drug in the pores at physiological temperature via self-assembling process and opened up the pores for drug release at elevated temperature via disassembling process. The doped ZnO@Fe3O4 nanoparticles core had excellent microwave-absorbing and thermal conversion property. On-demand drug release from this delivery system was realized not only by conventional heating but also by a noninvasive microwave radiation. In vitro results show that local heating generated by the core under microwave radiation was sufficient for release triggering while holding the bulk heating at physiological temperature. The controllable tissue-penetrating microwave stimuli combined with the tailor-made self-assembling peptide offer a new approach for thermal-responsive drug release.