Herein, hyperbranched poly(ethylene glycol)-based supramolecular nanoparticles with pH-sensitive properties were designed and used for targeted drug delivery. Via host–guest recognition between benzimidazole anchored poly(ethylene glycol)-hyperbranched polyglycerol (PEG-HPG-BM) and folic acid modified CD (FA-CD), targeted supramolecular nanoparticles (TSNs) were fabricated. At neutral aqueous conditions TSNs could load the model drug DOX. While under intracellular acidic conditions the loaded-drug would be released due to the protonation of BM. This protonation allowed the supramolecular nanoparticles to expand or even disassemble, which showes the pH-dependent property. The introduction of the active targeting FA molecule and the specific interactions with the receptor of HeLa cells means that DOX-loaded TSNs show a significantly improved anticancer efficacy. In vitro drug release assays and intracellular experiments confirmed that TSNs had an obvious pH-sensitive property and remarkably improved anticancer effects, which hold great potential for further biomedical applications such as anticancer drug delivery.