De Novo Design of Efficient NIR-II-Activated Heavy-Atom-Free Type-I Photosensitizer for Anti-Tumor Photoimmunotherapy

Type-I photosensitizers (PSs) are considered to be efficient agents for overcoming the oxygen-dependent deficiency of traditional photodynamic therapy (PDT). However, it is still challenging to design type-I PSs that can be activated by the second near-infrared (NIR-II) irradiation. Herein, a series of organic heavy-atom-free molecules are designed (named as CTU1, CTU2, and CTU3) and exhibit strong absorption bands over the first near-infrared and NIR-II regions. Among them, water-dispersible CTU3 nanoparticles (NPs) show strong J-aggregate characteristics and a good NIR-II absorption band, resulting in highly efficient •O₂ ^- generation upon irradiation of 1064 nm light. In addition, the CTU3 NPs also exhibit a high photothermal conversion efficiency of 88.6%. In vitro and in vivo experiments show that CTU3 NPs have superior PDT and photothermal therapy (PTT) effects, which can further induce immunogenic cell death and activate immune cells in 4T1 tumor-bearing mice for combined PDT/PTT anti-tumor photoimmunotherapy against refractory tumors. This work presents a paradigm of de novo design of NIR-II light-activated type-I PS for combinational photoimmunotherapy of cancer.