Supramolecular prodrugs that combine the merits of stimuli-responsiveness and targeting ability in a controllable manner have shown appealing prospects in disease diagnostics and therapeutics. Herein, we report that a new theranostic agent with the host-guest-binding-activated photosensitization has been fabricated by a binary supramolecular assembly consisting of the permethyl-β-cyclodextrin-grafted hyaluronic acid and a combretastatin A-4-appended porphyrin derivative. Illuminated by a red-light source, the production efficiency of singlet oxygen (1O2) pronouncedly increases by ∼60-fold once the porphyrin core is encapsulated by cyclodextrins. Consequently, the cell-selective fluorescence emission is dramatically enhanced, the microtubule-targeted drug is rapidly and completely released, and the 1O2-involved combinational treatment is simultaneously achieved both in vitro and in vivo. To be envisaged, this complexation-boosted light-activatable photosensitizing prodrug delivery system with improved photophysical performance and remarkable phototheranostic outcomes will make a significant contribution to the creation of more advanced stimulus-based biomaterials.