Novel hypercross-linked β-cyclodextrin nanospheres are rapidly synthesized with 4-amino-6-hydroxy-2-mercaptopyrimidine as a cross-linker within 5 min at a low temperature of 60 °C in the open water phase, thereby radically simplifying and accelerating the conventional time-consuming and environmentally harsh synthesis of cyclodextrin-containing polymers. The nanospheres demonstrate excellent and controllable performance as alkali-responsive nanocarriers and selective adsorbents for antibiotics.