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

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.