Albumin‐Chaperoned Deep‐NIR Triarylmethane Dyes for High‐Contrast In Vivo Imaging and Photothermal Therapy

Fluorophores absorbing/emitting in the deep near‐infrared (deep NIR) spectral region, that is, 800 nm and beyond, hold great promise for in vivo bioimaging, diagnosis, and phototherapy due to deeper tissue penetration. The bottleneck is the lack of bright, stable, and readily synthesized deep NIR fluorophores. Here, it is reported that the albumin‐chaperon strategy is a viable one‐for‐all strategy to address these difficulties. A focused library of deep‐NIR absorbing dyes (EA5) is easily synthesized via a two‐step cascade. They are neither very stable nor bright in phosphate buffer due to a propeller‐type flexible scaffold. Through screening, EA5_c3 is found to exhibit a high affinity toward bovine serum albumin (BSA). Binding‐associated structural rigidification resulted in a gigantic 26‐fold fluorescence enhancement. The albumin chaperone also greatly improved the stability of EA5_c3 by shielding the bisbenzannulated triarylmethane core from nucleophilic or oxidative species. The resulting EA5_c3@BSA exhibits high biocompatibility. It offered high‐resolution vasculature, lymph systems, tumors, and other tissue imaging with its bright deep NIR emission. At the same time, it exhibits prominent potential in photoacoustic imaging and photothermal treatment of subcutaneous and orthotopic breast tumors. These findings provide insights into robust and high‐performance fluorophores with deep NIR regions for theranostic against aggressive cancers. NIR‐phototherapy necessitates bright, stable, biocompatible fluorophores absorbing/emitting beyond 800 nm. Molecular engineering guidelines are established that brightness may be improved via rigidification, stability via steric shielding, and biocompatibility via the installation of multiple water‐soluble groups. Nevertheless, the resulting fluorochromic scaffold is expected to be synthetically challenging. BSA‐chaperoning of a structurally flexible deep NIR‐absorbing dye is a feasible solution to the problem.