Chemogenic albumin-seeking NIR dyes for in vivo site-specific albumin tagging

In vivo receptor tagging with contrast agent is considered an effective approach to achieve targeted bioimaging and imaging-guided surgery in the near-infrared-II (NIR-II) region, yet there has been a lack of systematic investigation into their binding mechanism for efficient in vivo targeted imaging. In this study, we design and synthesize a wide range of chemogenic albumin-seeking dyes to systematically investigate relationship between dye structures and binding behavior in situ. The albumin-seeking dye with optimized structures can undergo supramolecular interaction followed by covalent binding with albumin to form stable dye@albumin. This dye@albumin acts as an artificial fluorescent protein, in which a dye chromophore is wrapped by a natural protein that exists abundantly in living body. We further explain the much-improved photostability of dye@albumin from the perspective of photooxidation owing to their similar structures with classical fluorescent proteins. Among the synthesized albumin-seeking dyes, the optimized dye IR-6B5 exhibits comparable brightness and photostability to the previously reported IR-780, but offers superior NIR-II targeting bioimaging for tumors. Our designed albumin-seeking dyes enrich the NIR probe library and open up new possibilities for in vivo imaging and tumor-targeted guided surgery.