Supramolecular prodrug vesicles (H-4⊃B-2@MB) with selective antibacterial activity have been successfully constructed. Specifically, a natural antibiotic prodrug (B-2) with glutathione (GSH)-responsiveness was synthesized. The hydrophobic interaction between B-2 and a novel water-soluble cavitand with deep cavity (H-4) resulted in the formation of a host-guest complex, which further self-assembled into supramolecular vesicles. The formed vesicles could effectively encapsulate the photosensitizer methylene blue (MB), enabling co-delivery of antibiotics and photosensitizers in the presence of GSH. Moreover, upon excitation at 630 nm, the photosensitizers generate reactive oxygen species (ROS), effectively eradicating E. coli through combined chemo-photodynamic therapy. Considering that GSH is predominantly present in Gram-negative bacteria such as E. coli, this strategy exhibits substantial potential for selectively inhibiting bacteria characterized by high GSH levels to regulate bacterial colony equilibrium.