NIR‐II Protein‐Escaping Dyes Enable High‐Contrast and Long‐Term Prognosis Evaluation of Flap Transplantation

Abstract Real‐time vascular positioning, postoperative flap monitoring, and vascular reconstruction assessment are of great importance in flap transplantation. Cyanine dyes offer the advantage of high resolution in the Near‐infrared‐II (NIR‐II) imaging window. However, the nonspecific binding of many cyanine dyes to endogenous albumin leads to high organ accumulation and skin absorption, resulting in low‐quality imaging and poor reproducibility of contrast during long‐term (e.g., 7 days) postoperative monitoring. Here, a novel strategy is proposed that can be widely applied to prevent protein binding for NIR‐I/II Cl‐containing cyanine dyes. This strategy produces protein‐escaping dyes, ensuring high fluorescence enhancement in the blood with rapid clearance and no residual fluorescence, allowing for short‐term repeatable injections for vascular imaging. This strategy in the perioperative monitoring of pedicle perforator flap models in mice and rats is successfully applied. Furthermore, leveraging the universality of this strategy, multiple nonoverlapping protein‐escaping probes that achieve dual‐excitation (808 and 1064 nm) interference‐free imaging of nerve‐vessel and tumor‐vessel simultaneously are designed and synthesized. These protein‐escaping dyes enable long‐term repeatable dual‐color imaging of tumor localization, resection, and tumor‐vessel reconstruction at the wound site.