Ultra-small yet highly bright water-soluble single-benzene luminophore for glioblastoma surgical navigation

Creating ultra-small, water-soluble fluorophores with low molecular weight (<200 g mol^-1) is critical for bioimaging, as it enables high bioavailability, low toxicity, and penetration of physiological barriers-yet resolving the long-standing conflict between ultra-small size, bright emission, and robust photostability has remained a major bottleneck in this field. Here, we report a class of single-benzene skeleton luminophores that break this trade-off: they exhibit ultra-small molecular weights (the smallest so far), near-unity absolute quantum yields (up to 97% in aqueous solution), excellent water solubility, and exceptional photostability against photobleaching, temperature fluctuations (20-80 °C), pH variations (3-12), and ionic interference. The key structural innovations driving these properties are: (1) hydroxyl modifications that enhance water solubility without disrupting the conjugated system; (2) intramolecular F⋯H-O hydrogen bonds that rigidify the planar skeleton, suppressing vibrational relaxation and non-radiative decay. These dyes are synthesized via a gram-scale one-pot S_NAr reaction, avoiding tedious multi-step synthesis of conventional dyes. In preclinical studies, they demonstrate excellent biocompatibility (no toxicity in vitro up to 500 µM; no organ damage in vivo) and efficient blood-brain barrier penetration-critical for brain imaging. When applied to fluorescence-guided resection of orthotopic glioblastoma in mice, these dyes enable precise tumor margin delineation, reduce residual tumor burden by >90%, and extend median survival by 2.3-fold compared to saline controls (42 days vs. 18 days). This work not only provides a new generation of bioimaging probes for neurosurgical oncology but also establishes a general design strategy for ultra-small, high-performance fluorescent materials-laying a solid foundation for clinical translation in GBM surgery and beyond.