De Novo Construction of <i>pKa</i>‐Tunable Xanthene Molecules for pH Sensitive Fluorescence Navigation

Abstract pH is spatiotemporal variable dynamically in physiological and pathological processes, and the tiny pH changes can result completely different physiological processes. However, the major drawbacks of conventional pH‐activatable probes are their large acid‐base transition width and the challenge to adjust their pKa suitable for various application. In response to these issues, a novel approach is proposed to realize sensitive response and a general strategy to construct a multicolor and pKa‐tunable xanthene‐based platform. In these probes, the narrowest acid‐base transition range is just 1 pH units, achieved by introducing the electron‐rich pyridine as ingenious proton catcher. Especially, Si‐4Py owns near‐infrared (NIR) signal and pKa of 5.56, which is successfully used for the rapid and high‐contrast imaging of distal metastatic tumors. This has significant implications for guiding surgeons in the removal of these tumors and ultimately improve patient outcomes. Additional, the sustainably innovative strategy proposed by this work can serve as effective reference in pH probe development.