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

Abstract 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.