Heptamethine Cyanine‐Based Nanotheranostics with Catalase‐Like Activity for Synergistic Phototherapy of Cancer

Abstract Single‐molecule photosensitizers (PSs) for synergistic phototherapy are desirable but highly challenging, due to the competitive relationship between photothermal (PTT) and photodynamic therapy (PDT). Herein, a supramolecular strategy is developed that can tune the stacking pattern of PS molecules in their aggregates to optimize the PTT/PDT efficiency. Specifically, near‐infrared (NIR) heptamethine cyanines (Cy7) are synthesized using tricyanofuran (TCF) as the acceptor and benzothiazole (BTH)/indole (IND) as the donor, where BTH is a less hydrogen‐bonded tecton relative to IND. Both IND‐Cy7‐TCF and BTH‐Cy7‐TCF have similar photophysical properties at the molecular level, but BTH‐Cy7‐TCF in aggregated state exhibits higher singlet oxygen quantum yield (1.3% vs 0.2%) and competitive photothermal conversion efficiency (56.4% vs 62.3%) compared to IND‐Cy7‐TCF, due to the fine‐tuning of hydrogen bonding and intermolecular π–π interactions to form loose molecular stacks. Interestingly, the unique molecular stacking structure provides a binding site and catalytic center for H₂O₂ that exhibits catalase‐like activity, which can further ameliorate the efficiency of PDT and enhance the synergistic effect of PDT/PTT phototherapy in vitro and in vivo. This study can provide a simple but effective supramolecular strategy to design small molecule PSs with desirable aggregated structure for synergistic dual‐mode phototherapy.