Hydrophilization Strategies for Small-Molecule NIR-II Fluorophores towards Biological Imaging

Abstract

Second near-infrared (NIR-II, 1000–3000 nm) fluorescence imaging enables deep-tissue visualization with reduced photon scattering and suppressed tissue autofluorescence compared with visible and NIR-I imaging. The realization of long-wavelength absorption and emission, however, generally requires highly conjugated, conformationally rigid molecular backbones that inherently impart strong hydrophobicity. Since most biological applications occur in aqueous environments, small-molecule NIR-II fluorophores face key challenges, including limited water compatibility, uncontrolled aggregation, and fluorescence quenching. Hydrophilization is therefore a key molecular design factor for enabling their practical use in biomedicine. Herein, we systematically summarize hydrophilization strategies for small-molecule NIR-II fluorophores and discuss the structure–property–performance relationships that govern aqueous dispersibility, molecular packing, optical characteristics, and in vivo pharmacokinetics. Strategies for tuning aggregation behavior are further discussed to modulate emission wavelength, regulate intermolecular interactions, and enhance brightness in aqueous media. Finally, we outline emerging concepts for rational fluorophore hydrophilization and delivery and highlight future directions to improve clearance pathways, imaging precision, and the clinical translation potential of NIR-II imaging agents.