Monosaccharides play significant roles in daily metabolism in living organisms. Although various devices have been constructed for monosaccharide identification, most rely on the specificity of the natural enzyme. Herein, inspired by natural ionic channels, an asymmetrical MOF-in-nanochannel architecture is developed to discriminate monosaccharide enantiomers based on cascade reactions by combining oxidase-mimicking and Fenton-like catalysis in homochiral mesoporous CuMOF pockets. The identification performance is remarkably enhanced by the increased oxidase-mimicking activity of Au nanoparticles under a local surface plasmon resonance (LSPR) excitation. The apparent steady-state kinetic parameters and nano-fluidic simulation indicate that the different affinities induced by Au-LSPR excitation and the confinement effect from MOF pockets precipitate the high chiral sensitivity. This study offers a promising strategy for designing an enantiomer discrimination device and helps to gain insight into the origin of stereoselectivity in a natural enzyme. An asymmetrical architecture is developed to discriminate monosaccharide enantiomers based on enzyme-like cascade reactions in homochiral CuMOF pockets. The increased enzyme-like activity under LSPR excitation enhanced the identification performance.