How to reduce the cytotoxicity of antitumor peptides to normal cells remains an ongoing challenge. Here, we designed a pH/redox-responsive supramolecular structure (Pep-V subset of P-PEG) composed of a peptide modified with viologen (Pep-V) and polyethylene glycol bearing pillar[5]arene (P-PEG) as a "helmet". By shielding the hydrophobic moiety of the peptide derivative with pillar[5]arene via host-guest interactions, its disruption on normal cells can be effectively reduced. At acidic pH, the supramolecular structure can selectively adsorb onto negatively charged lipid membranes because of electrostatic interactions. Owing to redox responsiveness of the viologen group, Pep-V could be separated from P-PEG after the addition of reductants and inserted into lipid bilayers, which leads to membrane disruption. Cargo leakage of liposome models was investigated to understand Pep-V subset of P-PEG-induced liposomal membrane disruption under different pH values and redox conditions. Results showed that Pep-V subset of P-PEG caused almost no cargo leakage from (1,2-dipalmitoyl-sn-glycerol-3-phosphocholine) liposomes at pH 7.4 but significant leakage from negatively charged (1,2-dipalmitoyl-sn-glycerol-3-phospho-(1-rac-glyerol)) liposomes at pH 5.0 under a reducing environment. Pep-V subset of P-PEG displayed low destructive effects on mimic normal cells and significant disruption to mimic tumor cells when exposed to a reducing environment that is expected to be a potential antitumor agent.