Molecular Engineering of AIE Photosensitizers for Enhanced Antitumor Phototheranostics.

Cancer remains a major threat to global public health, highlighting the urgent need for precise and effective treatment strategies. Photothermal therapy (PTT) has gained increasing attention as a promising alternative owing to its non-invasiveness, deep tissue penetration, and oxygen-independent mechanism. However, the development of high-performance organic photothermal agents (PTAs) with pronounced near-infrared absorption, high photothermal conversion efficiency (PCE), and good photostability remains challenging. Herein, we propose a synergistic strategy combining π-bridge and donor engineering to design a series of aggregation-induced emission (AIE)-active small-molecule photosensitizers. Experimental and theoretical analyses reveal that stepwise introduction of a planar thiophene π-bridge and methoxy donor groups systematically regulates the excited-state energy dissipation pathways, enabling a continuous modulation from photodynamic therapy (IsoTPA), through balanced synergistic PDT/PTT (IsoTHTPA, PCE = 57.2%), to highly efficient PTT (IsoTHTO, PCE = 64.3%), which reveals the fundamental competitive interplay between intersystem crossing and non-radiative decay. Encapsulated into nanoparticles, IsoTHTO NPs demonstrate efficient photothermal ablation of 4T1 tumor cells and significant tumor growth inhibition under 660 nm laser irradiation both in vitro and in vivo. This work presents a reasonable molecular design approach for tunable access to PDT, synergistic PDT/PTT, and PTT modalities from a single molecular platform for cancer phototheranostics.