Bandgap Modulation and Lipid Intercalation Generates Ultrabright D–A–D-Based Zwitterionic Small-Molecule Nanoagent for Precise NIR-II Excitation Phototheranostic Applications

Conjugated small-molecule (CSM) phototheranostic agents that operate in the second near-infrared (NIR-II) region have garnered significant attention in the field of biomedicine. However, a lack of fluorescence-emitting ability hinders their use in precise fluorescence imaging (FI)-guided photothermal therapy (PTT). Herein, a two-pronged fluorescence intensification strategy—molecular engineering for rational bandgap modulation and lipid-intercalation to combat fluorescence quenching—is used to develop NIR-II-excited ultrabright donor–acceptor–donor-based (D–A–D)-based zwitterionic CSM nanoagent for tumor phototheranostics. The molecular engineering strategy produces the NIR-II-excited D–A–D-based zwitterionic fluorophore (BTFQ) that exhibits a high NIR-II fluorescence quantum yield (QY = 0.65%) in dichloromethane. More importantly, BTFQ complexed with liposome (DMPC) to form the zwitterion–liposome nanoagent (BTFQ/DMPC) shows a negligible loss of QY (0.63%) in aqueous media. Moreover, because BTFQ/DMPC possesses excellent photothermal conversion efficiency (PCE = 30.8%) performance, it can be used to realize efficient in vivo 1064 nm single-photon high-resolution NIR-II FI guided NIR-II PTT. This study introduces a new avenue for the development of NIR-II-excited NIR-II FI/PTT agents for precise and effective tumor treatment.