The constructing of novel supramolecularprodrug nanoparticlesbased on the host–guest interaction of water-soluble pillar[6]arene(WP6) and novel doxorubicin (DOX)-based prodrugs (G1or G2) is reported, in which these two kindsof prodrugs are synthesized by conjugating DOX with a flexible alkylchain or a short EGnchain via an acid-cleavable hydrazonebond. The obtained supramolecular nanoparticles are stable under physiologicalconditions, whereas the cumulative release of DOX is approximate to100% within 30 min at pH 5.5 by simulating the endolysosomal environmentat 37 °C. It is noteworthy that WP6can efficientlycatalyze the cleavage of hydrazone bond of the prodrug G1or G2via a favored intramolecular process under acidicconditions. Moreover, intracellular localization experiments demonstratedthat these two nanoparticles, taken up by cancer cells via endocytosis,can lead to efficient DOX accumulation in SKOV3 cancer cells. Cytotoxicityexperiments further suggest that these nanoparticles can efficientlyinhibit the proliferation of cancer cells and exhibit potent antitumoractivity. [ABSTRACT FROM AUTHOR]