A new type of guest-core supramolecular networks via inclusion complexation of nanoscaled building blocks such as bifunctional cyclodextrin (CD) derivatives and trifunctional melamine derivatives were prepared. By using AFM and an adoption of the cryo-TEM technique under high acceleration voltage the nanoscale supramolecular network structure, nexus units, and CD molecules could be visualized. In addition to the 2-D H-1 NMR rotating frame Overhauser effect spectroscopy (ROESY) experiments, theoretical studies on the molecular docking of the CDs and the melamine derivative have been conducted to elucidate the thermodynamic properties by the two-layered integrated molecular orbital and molecular mechanics (ONIOM) method, which combines both quantum mechanics and molecular mechanics (QM/MM) calculations.