An aqueous-soluble melamine polymer was condensed into nanoparticles by specific heterocycle binding interactions with 5-fluorouracil (5-FU) or cyanuric acid (CA). Small-molecule/polymer recognition of this type exhibits a clear exothermic binding signature and is sufficiently robust to induce macromolecular assembly in water. Polymer amphiphiles with melamine sites in the hydrophobic block could be stably loaded with up to 17% weight 5-FU. Macromolecular assembly with 5-FU or CA requires specific hydrogen-bonding recognition between 5-FU/CA and polymer-displayed melamine; assembly may be blocked by melamine methylation. Melamine and 5-fluorouracil complexes were analyzed by X-ray crystal structure determination, which revealed the expected 5-FU/melamine hydrogen-bonding interactions.