We report herein a l-glutamate (l-Glu)-responsive delivery system. It consists of Janus Au-mesoporous silica (MS) nanoparticles functionalized with l-glutamate oxidase on the Au face and with self-immolative arylboronate derivatives as caps on the MS face. The MS face is additionally loaded with a cargo. The delivery paradigm is based on the recognition of l-Glu by the enzyme and the subsequent formation of H2O2, which induces the cleavage of the self-immolative gate and the uncapping of the pores. Given the importance of l-Glu as a key neurotransmitter, we hope that these findings will help in designing new therapeutic strategies for nervous system diseases.