Molecular Engineering of Strong Electron‐Deficient Acceptor for Constructing D‐A Conjugated Polymers in NIR‐II Photothermal Therapy

ABSTRACT Traditional conjugated polymers are restricted to near‐infrared‐I (NIR‐I, 780–900 nm) absorption, limiting their utility in photothermal therapy (PTT) for deep‐seated tumors. To address this challenge, we rationally engineered a pyrazine‐functionalized BDOPV‐based acceptor (PzBDOPV) with strong electron‐deficient properties and constructed two donor‐acceptor (D‐A) conjugated polymers: PPzBDOPV‐T (P1) and PPzBDOPV‐BT (P2). Density functional theory (DFT) calculations revealed that pyrazine induces dual structural optimization: (1) lowering the lowest unoccupied molecular orbital (LUMO) to −4.10 eV, thereby enhancing intramolecular charge transfer (ICT); and (2) establishing S⋯N noncovalent interactions (bond length 2.94 Å), which reduce the conjugated backbone dihedral angle from ∼24° (in BDOPV) to ∼3°, improving electron delocalization. These modifications yield NIR‐II absorption maxima at 955 nm (P1) and 907 nm (P2) in THF. Nanoparticles (NPs) formulated via DSPE‐PEG 2000 encapsulation (NP1 and NP2) exhibit excellent photothermal performance under near‐infrared‐II (NIR‐II) region laser irradiation (980 nm, 0.6 W·cm − 2 ). In vitro studies confirmed >90% viability of 4T1 cells at 150 µg mL − 1 (dark conditions) and >80% apoptosis induction upon laser treatment. In vivo, NP1‐mediated PTT achieved complete tumor regression (56.4°C peak temperature) without systemic toxicity, while photoacoustic imaging provided clear tumor delineation. This work establishes a robust molecular design paradigm for NIR‐II‐absorbing conjugated polymers, advancing safe and effective theranostic agents for deep‐tissue cancer treatment.