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

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-PEG₂₀₀₀ 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.