Novel cyclodextrin-prodrug supramolecular nanoparticles (NPs) with cooperative-enhancing cancer therapy were constructed from a reduction-sensitive disulfide bond-linked permethyl-beta-cyclodextrin-camptothecin prodrug, water-soluble adamantane-porphyrin photosensitizer, and hyaluronic acid grafted by triphenylphosphine and beta-cyclodextrin through an orthogonal host-guest recognition strategy, displaying uniform nanoparticles with a diameter around 100 nm as revealed by dynamic light scattering, transmission electron microscopy, scanning electron microscopy, and atomic force microscopy. Compared with 293T normal cells, the supramolecular NPs could be easily taken up by mitochondria of A549 cancer cells, then release the active anticancer drug camptothecin (CPT) in situ via the cleavage of the disulfide bond by the overexpressed glutathione, and could initiate the effective singlet oxygen (O-1(2)) generation by porphyrin under light irradiation, ultimately resulting in severe mitochondrial dysfunction and a rising cell death rate with increasing micromolar concentration of NPs. These multicomponent supramolecular nanoassemblies effectively combined the two-step synergistic chemo-photodynamic therapy of reduction-release of CPT and light-triggered O-1(2) generation within cancer cells presenting the synergistic effect of supramolecular nanoparticles on cancer therapy, which provide a new approach for efficient step-by-step cancer therapy.