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 near-infrared (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.