Cyanopyrazine‐Scaffold Phototheranostic Agents Featuring Type‐I Photosensitization and Photothermal Conversion for Synergistic Tumor Phototherapy

ABSTRACT

Synergistic type‐I photodynamic and photothermal therapies have emerged as promising strategies for treating hypoxic tumors. However, the development of high‐performance type‐I photosensitizers that simultaneously achieve efficient radical reactive oxygen species (ROS) generation and strong photothermal conversion remains challenging, due to limited molecular design strategies and unclear structure‐property relationships. Herein, we develop a rigid and strongly electron‐deficient acenaphtho[1,2‐ b ]pyrazino[2,3‐ e ]pyrazine‐9,10‐dicarbonitrile (APzCN) acceptor, and construct three donor‐acceptor‐structural molecules ( APzCN‐DTPA , APzCN‐MeOTPA , and APzCN‐TPA ) by pairing it with different arylamine donors. These compounds exhibit pronounced intramolecular charge transfer (ICT) and broad near‐infrared absorption. The remarkable ICT effect and the resulting spatial separation of frontier molecular orbitals facilitate radical‐type ROS generation, whereas the vigorous intramolecular motions induced by the APzCN scaffold regulate photothermal conversion. Among the compounds, APzCN‐DTPA shows efficient pure type‐I ROS (•OH and •O ₂ ⁻ ) production and a high photothermal conversion efficiency of 55.1% under 660 nm irradiation. Quantum chemical calculations reveal that the narrow singlet‐triplet splitting (below 0.10 eV), multiple intersystem crossing channels mediated by higher‐lying triplet states, and strong ICT synergistically promote type‐I photosensitization, while abundant carbon‐nitrogen bond‐stretching vibrations of the APzCN segment enhance the photothermal effect. In addition, it demonstrates lysosomal accumulation, robust intracellular •OH and •O ₂ ⁻ generation, and potent photothermal imaging‐guided antitumor efficacy both in vitro and in vivo, while maintaining good biosafety.