Four mixed cyclodextrin‐calixarene nanosponges were tested as possible Drug Delivery Systems, using Tetracycline antibiotic as a suitable model drug. The selected nanosponges featured a different composition ratio between the two host co‐monomer components, and the possible presence of ionisable amine or carboxyl groups deriving from chemical post‐modification. The pH‐dependent absorption and release abilities of the materials were verified; in particular release kinetics showed the occurrence of a simple first‐order profile. The antibacterial activity of nanosponge‐tetracycline composites suitably prepared under sterile conditions was assayed towards both Gram‐positive and Gram‐negative typical bacterial strains, showing in some cases an interesting improvement of the biocidal activity.