Protein@Cyanine‐Based NIR‐II Lymphography Enables the Supersensitive Visualization of Lymphedema and Tumor Lymphatic Metastasis

Abstract Visualization of the lymphatic system is clinically indispensable for the diagnosis and/or treatment of lymphatic diseases. Although indocyanine green (ICG) lymphography becomes an alternate imaging modality compared to traditional lymphoscintigraphy, it is still far from ideal due to the insufficient detection depth and low spatiotemporal resolution. Herein, protein@cyanine probes are rationally developed to solve the limitations of the current near‐infrared‐I (NIR‐I) lymphography. The protein@cyanine probes are synthesized following a chlorine‐containing dye‐labeling strategy based on structure‐selectivity (facile covalent binding between the dye and protein with a 1:1 molar ratio). As expected, the probes display exceptional NIR‐II imaging ability with much‐improved imaging contrast/resolution and controllable pharmacokinetics, superior to the clinical ICG. The protein@cyanine probes locate lymph nodes and delineate lymphatic vessels with super‐high sensitivity and signal‐to‐background ratio, enabling real‐time diagnosing lymphatic diseases such as lymphedema and tumor lymphatic metastasis. In particular, the NIR‐II lymphography provides an opportunity to discover the disparate morbidity rate of primary lymphedema in different types of mice. Given the fact of lacking clinically transferable NIR‐II probes, this work not only provides a promising strategy for enriching of the current library of NIR‐II probes, but also promotes the clinical translation of NIR‐II lymphography technology.