Engineering Simple Type I AIE Photosensitizer via Donor and π ‐Bridge Modulations for NIR‐II Imaging‐Guided Photodynamic and Photothermal Therapy

Abstract Imaging‐guided synergetic photodynamic‐photothermal therapy is growing into a sparkling frontier in cancer treatment by virtue of its high precision and minimally invasive nature. However, clinical application remains limited by the oxygen dependence of conventional photosensitizers (PSs) and the poor tissue penetration of light. There is thus a growing demand for PSs with reduced oxygen dependence and enhanced emission properties, particularly within the second near‐infrared (NIR‐II) window. In this study, a Type I aggregation‐induced emission (AIE) photosensitizer, MDPA‐T‐TCP is presented, designed by precisely engineering a 4,4′‐methoxydiphenylamine donor and a thiophene π ‐bridge. This design, featuring a twisted donor moiety, the planar configuration of π ‐bridge paired with a thiadiazole‐cyanopyridine acceptor, strengthens the donor–accepter interactions, significantly enhancing NIR‐II fluorescence and boosting hydroxyl radical production compared to PSs with methoxy‐free donors or phenyl π ‐bridges, as confirmed by both experimental and theoretical analyses. MDPA‐T‐TCP also exhibits considerable photothermal conversion efficiency, further enhancing its dual therapeutic and diagnostic potential. In vivo and in vitro experiments demonstrate that MDPA‐T‐TCP nanoparticles enable effective NIR‐II imaging‐guided synergetic photodynamic‐photothermal therapy, achieving successful tumor ablation. This finding provides valuable insights into the development of simple, versatile, and clinically promising NIR‐II AIE‐based phototheranostic agents.