Nonconjugated Structural Distortion Promoting the Formation of NIR Triplet states in Phenothiazine Dyes for Cancer Photoimmunotherapy.

Abstract

Near-infrared (NIR) triplet-state dyes are pivotal for advanced biomedical and material science applications. Although numerous strategies have been proposed to enhance the photosensitization efficiency of dyes, significant challenges remain. Herein, we propose a novel strategy leveraging nonconjugated structural distortion to enhance triplet-state formation. This strategy, achieved by introducing steric groups at the edges of the phenothiazine (PTZ) dye framework, notably enhances intersystem crossing (ISC) and prolongs triplet-state lifetime. Based on this strategy, HNBS and HNBSe are synthesized, which exhibit exceptional triplet-state quantum yields (47.2% for HNBS and 87.7% for HNBSe) and prolonged triplet-excited-state lifetimes (21.1 μs for HNBS and 6.3 μs for HNBSe). These values substantially exceed those of conventional dyes, such as NBS (negligible and NBSe (3.2 μs). Under ultralow-light doses (0.45 J/cm2 in vitro, 6 J/cm2 in vivo), these photosensitizers demonstrate robust tumor cell inhibition, highlighting their exceptional photosensitizing ability. Mechanistically, HNBS possesses lysosomal-targeting ability, and upon light irradiation, it induces lysosomal damage, triggering pyroptosis and immunogenic cell death. These processes promote dendritic cell maturation and T-cell differentiation, augmenting the immune response and enabling effective photoimmunotherapy.