Effective One-for-All Phototheranostic Agent for Hypoxia-Tolerant NIR-II Fluorescent/PA Image-Guided Phototherapy

Near-infrared (NIR)-triggered type-I photosensitizers are crucial to address the constraints of hypoxic tumor microenvironments in phototherapy; however, significant challenges remain. By selecting an electron-deficient unit, a matched energy gap in the upper-level state is instrumental in boosting the efficiency of intersystem crossing for the type-I electron transfer process. 2-Cyanothiazole, an electron acceptor, is covalently linked with N, N-diphenyl-4-(thiophen-2-yl)aniline to yield a multifunctional photosensitizer (TTNH) that exhibits intrinsic NIR absorbance and compatible T₂ energy levels, facilitating both radiative and nonradiative transitions. The prepared nanoparticles (TTNH NPs) assembled from TTNH are activated by an 808 nm laser and generated the O₂•^- for hypoxia-tolerant type-I photodynamic therapy under both normoxia and hypoxic conditions. TTNH NPs emitted NIR-II fluorescence with an impressive NIR-II fluorescence quantum yield of 2.08%. With a high photothermal conversion efficiency of 51.8% under 808 nm laser stimulation, TTNH NPs exhibit photothermal therapy performance, accompanied by enhanced photoacoustic imaging capability owing to their strong NIR absorption. These characteristics make TTNH an effective NIR-wavelength-triggered phototheranostic agent that outperforms NIR-II fluorescence/photoacoustic dual-model imaging-guided type-I photodynamic therapy/photothermal therapy against hypoxic tumors. This results provide valuable insight for developing high-performance NIR-II-emissive superoxide radical phototheranostic agents.