Molecular Scaffolding Engineering Generates High‐Efficiency Anti‐Quenching Small Molecules for NIR‐IIb Fluorescence Imaging and Phototheranostic Applications

ABSTRACT Small‐molecule fluorophore‐based phototheranostics hold great promise, particularly those emitting in the second near‐infrared window IIb (NIR‐IIb, 1500–1700 nm). However, the rational design of such molecules remains a formidable challenge. Here, we propose a molecular spatial scaffolding strategy to precisely modulate donor‐acceptor‐donor (D–A–D)‐type fluorophores, resulting in the development of an optimized phototheranostic agent, termed TPCTP NPs. The introduction of rationally designed spatial scaffolding units preserves the planarity of the conjugated molecular core while suppressing undesired π‐π stacking. This structural optimization conferred a high molar extinction coefficient (1.2 × 10 4 M − 1 cm − 1 ), an enhanced fluorescence quantum yield (0.18%), and good NIR‐IIb fluorescence imaging (FLI) performance. Moreover, the aromatic scaffold unit promote intramolecular motion, thereby improving the photothermal conversion efficiency (PCE = 45.6%) and enabling effective tumor ablation. Collectively, these attributes render TPCTP NPs a promising platform for NIR‐IIb FLI/photothermal imaging (PTI)‐guided photothermal therapy.