Smart Self‐Assembly Amphiphilic Cyclopeptide‐Dye for Near‐Infrared Window‐II Imaging

Development of novel nanomaterials for disease theranostics represents an important direction in chemistry and precision medicine. Fluorescent molecular probes in the second near‐infrared window (NIR‐II, 1000–1700 nm) show high promise because of their exceptional high detection sensitivity, resolution, and deep imaging depth. Here, a sharp pH‐sensitive self‐assembling cyclopeptide‐dye, SIMM1000, as a smart nanoprobe for NIR‐II imaging of diseases in living animals, is reported. This small molecule assembled nanoprobe exhibits smart properties by responding to a sharp decrease of pH in the tumor microenvironment (pH 7.0 to 6.8), aggregating from small nanoprobe (80 nm at pH 7.0) into large nanoparticles (>500 nm at pH 6.8) with ≈20–30 times enhanced fluorescence compared with the non‐self‐assembled CH‐4T. It yields micrometer‐scale resolution in blood vessel imaging and high contrast and resolution in bone and tumor imaging in mice. Because of its self‐aggregation in acidic tumor microenvironments in situ, SIMM1000 exhibits high tumor accumulation and extremely long tumor retention (>19 days), while being excretable from normal tissues and safe. This smart self‐assembling small molecule strategy can shift the paradigm of designing new nanomaterials for molecular imaging and drug development. The complex and ambiguous chemical formulas of the majority of traditional nanoparticles stand in the way of their clinical translation. A small‐molecular‐based sharp pH‐responding fluorescent nanoprobe for NIR‐II imaging of various tumor models with high signal‐to‐background ratio and long retention time is developed. This nanoparticle's definite chemical structure and simple production process properties highly increase its clinical translation potential.