Synergistic S···O and S···H Conformational Locks for Planarity‐Enhanced NIR‐II Phototheranostics

Abstract Achieving strong near‐infrared (NIR) absorption while retaining high fluorescence efficiency remains a central challenge in developing organic phototheranostic agents, as enhanced π‐conjugation planarity often aggravates aggregation‐caused quenching. Here, a synergistic noncovalent conformational lock (NCL) strategy is introduced that simultaneously enhances molecular planarity, increases rigidity, and preserves NIR‐II fluorescence. Three benzobisthiadiazole (BBT)‐derived dyes, SBT, SBTTh, and SBTTPA, are designed with progressively introduced S···O and S···H interactions to modulate conformation and optoelectronic properties. The dual locks in SBTTPA efficiently reinforced intramolecular rigidity, narrowed the bandgap, and induced a pronounced bathochromic shift, driving emission into the NIR‐II window. Notably, SBTTPA nanoparticles (NPs) achieved a fluorescence quantum yield of 4.36% (IR1061 as reference) and an ultrahigh fluorescence brightness of 671.44 M −1 cm −1 , representing a 4.6‐fold improvement over SBTTh NPs. Beyond fluorescence, SBTTPA NPs exhibited superior photothermal conversion efficiency (38%) and robust type I reactive oxygen species generation (O 2 •− and •OH) under photoirradiation. In vitro and in vivo evaluations confirmed their excellent NIR‐II fluorescence/photoacoustic imaging capabilities and potent therapeutic efficacy. This study establishes, for the first time, that cooperative S···O and S···H conformational locks effectively resolve the planarity‐fluorescence paradox, offering a general molecular design strategy for bright NIR‐II chromophores in advanced phototheranostics.