A supramolecular nanoprodrug (DOX@GP5⊃Pro-NFA) was constructed based on the host-guest complexation of chloride channel blocker prodrug (Pro-NFA) and glycosylated pillar[5]arene (GP5), which could target tumor cells via galactose and release DOX/NFA responsively under esterase stimulation. In vitro studies revealed that this supramolecular nanoprodrug can overcome drug resistance through inhibiting chloride channels as well as inhibiting the migration of HepG2/ADR cells. This strategy can therefore achieve enhanced potency in chemotherapy through reverse chemoresistance.