Highly Emissive NIR-II Unimolecular Micelles via a Core–Cap Synthetic Strategy for Deep-Tissue Imaging and Image-Guided Surgery

High-performance fluorescence imaging in the second near-infrared (NIR-II, 1000–1700 nm) window holds promise for deep-tissue optical diagnostics. However, simultaneously achieving high fluorescence quantum yields (QYs) and ultrasmall dimensions in physiological aqueous environments remains a fundamental challenge. Here, we report a de novo core–cap synthetic strategy to construct highly emissive, renal-clearable NIR-II fluorophores based on a unimolecular micelle architecture. By integrating a rigid, donor–acceptor–donor (D–A–D) hydrophobic core containing orthogonal axial and lateral steric shielding networks with a hydrophilic polyethylene glycol (PEG) outer cap, we successfully suppress water-induced nonradiative decay and intermolecular aggregation-induced quenching without compromising lateral conjugation. Molecular dynamics simulations and experimental characterizations reveal that these amphiphilic structures self-assemble into highly monodisperse unimolecular micelles featuring an ultrasmall hydrodynamic diameter of ∼5 nm. The optimized fluorophore exhibits a peak NIR-II emission centered at 1034 nm with a high aqueous QY of 4.6%. Owing to their sub-5 nm dimensions, unimolecular micelles undergo dual renal and hepatic clearance pathways, circumventing the biosafety concerns of prolonged tissue retention typical of conventional nanoparticles. Capitalizing on their high brightness, we demonstrate high-resolution, contrast-enhanced in vivo imaging of systemic and cerebral vasculatures, allowing the quantitative morphometric visualization of structural abnormalities in transgenic brain tumors. Furthermore, these fluorophores enable high-contrast, intraoperative fluorescence-guided tumor resection with clearly defined margins. This work provides a promising strategy for the rational design of bright, fast-clearing organic NIR-II probes for advanced biomedical diagnostics.