In recent years, the rational design and construction of drug delivery systems (DDSs) via a supramolecular approach for improving chemical therapeutics have gained significant attention. Here, we report a host-guest DDS formed from a fluorescent, chirality-responsive, and water-soluble tetraphenylethene-based octacationic cage as a fluorescent/chiral probe, solubilizer, and molecular cargo, which can recognize chiral nucleoside drugs, enhance the solubility of insoluble drugs, and protect drugs from the outside environment by forming host-guest complexes in aqueous solution. Given the fluorescence properties and dynamically rotational conformation of tetraphenylethene (TPE) units, this fluorescent and chirality-responsive cage exhibits different responses including turn-on/turn-off fluorescence and negative/positive circular dichroism (CD) when binding with different chiral nucleoside drugs in water, resulting in multiple-responsive photophysical behaviors for these chiral drugs. Furthermore, this water-soluble cationic cage with a hydrophobic cavity can improve the water solubility of insoluble drugs (e.g., CPT) by forming host-guest complexes in water. More importantly, this multifunctional cage exhibits a low toxicity to both human colon and breast cancer cell lines in vitro, and drugs encapsulated by the cage are more effective in killing cancer cells than drugs alone. Finally, the on-off-on fluorescence responses in the formation and dissociation processes of the cage⊃drug complexes have been successfully used to monitor drug release and track drug delivery by fluorescence microscopy in vitro. Therefore, this fluorescent, chirality-responsive, and water-soluble cage as a multifunctional molecular container can be used to construct a smart drug delivery system with several functions of fluorescence and CD detection, water solubilization, real-time monitoring, and chemotherapy.