Near‐Infrared Chemiluminophore Switches Photodynamic Processes via Protein Complexation for Biomarker‐Activatable Cancer Therapy

Despite the potential in cancer therapy, phototheranostic agents often face two challenges: limited diagnostic sensitivity due to tissue autofluorescence and suboptimal therapeutic efficacy due to the Type‐II photodynamic process with the heavy oxygen reliance. In contrast, chemiluminescent theranostic agents without the requirement of real‐time light excitation can address the issue of tissue autofluorescence, which however have been rarely reported for photodynamic therapy (PDT), not to mention less oxygen‐dependent Type‐I PDT. In this work, we synthesize NIR chemiluminophores with the specific binding towards human serum albumin (HSA) to form chemiluminophore‐protein complex for cancer detection and photodynamic therapy. Interestingly, after the complexation with HSA, the chemiluminescence (CL) intensities of chemiluminophores are enhanced by over 10‐fold; meanwhile, the photodynamic process switches from Type‐II (singlet‐oxygen‐generation dominated) to Type‐I (superoxide anion and hydroxyl radical dominated), while the previously reported activated chemiluminophore with non‐specific HSA binding can’t switch photodynamic process. Based on the optimal chemiluminophore, a nitroreductase‐activatable CL probe‐protein complex is synthesized, which specially turns on its CL and Type‐I PDT in hypoxic tumors for precision therapy. Thus, this study provides a complexation strategy to improve phototheranostic performance of chemiluminophores.