Polymethine Chromophores for NIR-II Phototheranostics: From Molecular Engineering to Nanoformulation-Enabled Bioapplications

Polymethine chromophores, particularly cyanine and cyanine-like dyes, have emerged as key molecular platforms for bioimaging in the second near-infrared window (NIR-II) owing to their tunable long-wavelength absorption and emission, high molar absorptivity, and modular structural programmability. Advances in chain engineering, end-group modification, and donor-acceptor modulation have substantially expanded the chemical space of polymethine-based NIR-II fluorophores and enabled improved control over their optical properties and excited-state behavior. However, favorable molecular photophysics do not necessarily translate into reliable biological performance, as free polymethines remain vulnerable to aggregation-caused quenching, solvatochromic instability, biomolecular interference, unfavorable in vivo fate, and limited photostability. Nanoformulation has, therefore, become a central strategy for bridging molecular design and biological function. By regulating intermolecular packing, protecting the fluorophore microenvironment, optimizing pharmacokinetics and biodistribution, and enabling the integration of targeting, activatable responses, multimodal imaging, and therapy, nanoformulated polymethines have evolved from simple fluorescent dyes into adaptable NIR-II imaging and theranostic platforms. This review summarizes recent progress in molecular engineering, barriers to direct biological application, and nanoformulation-enabled imaging and theranostic applications and discusses remaining challenges and future opportunities for translational development.