Supramolecular Chiral Binding Affinity‐Achieved Efficient Synergistic Cancer Therapy

Abstract Supramolecular chirality‐mediated selective interaction among native assemblies is essential for precise disease diagnosis and treatment. Herein, to fully understand the supramolecular chiral binding affinity‐achieved therapeutic efficiency, supramolecular chiral nanoparticles (WP5⊃D/L‐Arg+DOX+ICG) with the chirality transfer from chiral arginine (D/L‐Arg) to water‐soluble pillar[5]arene (WP5) are developed through non‐covalent interactions, in which an anticancer drug (DOX, doxorubicin hydrochloride) and a photothermal agent (ICG, indocyanine green) are successfully loaded. Interestingly, the WP5⊃D‐Arg nanoparticles show 107 folds stronger binding capability toward phospholipid‐composed liposomes compared with WP5⊃L‐Arg. The enantioselective interaction further triggers the supramolecular chirality‐specific drug accumulation in cancer cells. As a consequence, WP5⊃D‐Arg+DOX+ICG exhibits extremely enhanced chemo‐photothermal synergistic therapeutic efficacy (tumor inhibition rate of 99.4%) than that of WP5⊃L‐Arg+DOX+ICG (tumor inhibition rate of 56.4%) under the same condition. This work reveals the breakthrough that supramolecular chiral assemblies can induce surprisingly large difference in cancer therapy, providing strong support for the significance of supramolecular chirality in bio‐application.