A Hypoxia‐Activated Diketopyrrolopyrrole‐Based Single‐Molecule Prodrug for Combined Chemotherapeutic and Type‐I Photodynamic/Photothermal Trimodal Cancer Therapy

Hypoxia, as a unique tumor microenvironment, offers an opportunity for the development of activatable therapeutic agents. However, most current activatable agents are confined to monotherapy, limiting their overall efficacy. We herein report a novel single-molecule prodrug for hypoxia-activated trimodal cancer therapy. A diketopyrrolopyrrole-based molecule (AMO) was first synthesized, demonstrating efficient type-I photodynamic (PDT) and photothermal (PTT) activities. To integrate chemotherapy, a hypoxia-cleavable azo linker was introduced to conjugate a cytotoxic drug, nitrogen mustard, yielding the prodrug AIO. Under normoxic conditions, the AIO exhibited attenuated phototherapeutic effects, minimizing off-target toxicity. In contrast, the hypoxic tumor environment triggered azo cleavage, releasing the chemotherapeutic agent while simultaneously restoring type-I PDT and PTT functionalities. This work provides an activatable trimodal combination therapeutic strategy with promising translational potential for precise cancer treatment.