Ultrabright NIR‐II Nanoparticles for High‐Resolution In Vivo Imaging: From Systemic Vasculature Visualization to Pathological Microenvironment Monitoring

Abstract Highly emissive fluorescence probes are crucial for precise disease diagnosis. To overcome the persistent limitations of low quantum yield in near‐infrared‐II (NIR‐II) organic dyes, an aggregation‐induced emission (AIE) luminogen, TPE‐Hexoxyl, has been strategically designed. By synergistically suppressing π ‐ π stacking and minimizing intramolecular charge transfer, we engineered NIR‐II nanoparticles that rank among the brightest organic probes reported (absolute Φ PL = 0.9%). In vitro studies demonstrated that TPE‐Hexoxyl nanoparticles exhibit exceptional colloidal stability and remarkable photostability. In vivo imaging displayed its high spatial resolution and prolonged tissue retention, enabling dynamic high‐contrast visualization of systemic vasculature, cerebral microvasculature, and lymphatic networks. Remarkably, TPE‐Hexoxyl nanoparticles show superior sensitivity in detecting tumor lesions in orthotopic 4T1 tumor‐bearing mice models and achieve precise spatial mapping of inflammatory regions in inflammatory bowel disease models, underscoring their transformative potential for clinical pathological diagnostics. This work establishes a molecular modulation paradigm for designing high‐brightness organic NIR‐II fluorophores, providing an advanced molecular tool for further clinical diagnostic applications.