Alkyl chain length-regulated in situ intelligent nano-assemblies with AIE-active photosensitizers for photodynamic cancer therapy

Photodynamic therapy (PDT) brings new hope for the treatment of breast cancer due to few side effects and highly effective cell killing; however, the low bioavailability of traditional photosensitizers (PSs) and their dependence on oxygen severely limits their application. Aggregation-induced emission (AIE) PSs can dramatically facilitate the photosensitization effect, which can have positive impacts on tumor PDT. To-date, most AIE PSs lack tumor targeting capability and possess poor cell delivery, resulting in their use in large quantities that are harmful to healthy tissues. In this study, a series of AIE PSs based on pyridinium-substituted triphenylamine salts ( TTPAs <b>1</b>-<b>6</b>) with different alkyl chain lengths are synthesized. Results reveal that TTPAs <b>1</b>-<b>6</b> promote the generation of type I and II ROS, including ·OH and ¹O₂. In particular, the membrane permeability and targeting of TTPAs <b>4</b>-<b>6</b> bearing C8-C10 side-chains are higher than TTPAs <b>1</b>-<b>3</b> bearing shorter alkyl chains. Additionally, they can assemble with albumin, thereby forming nanoparticles (TTPA <b>4</b>-<b>6</b> NPs) <i>in situ</i> in blood, which significantly facilitates mitochondrial-targeting and strong ROS generation ability. Moreover, the TTPA <b>4</b>-<b>6</b> NPs are pH-responsive, allowing for increased accumulation or endocytosis of the tumor and enhancing the imaging or therapeutic effect. Therefore, the <i>in vivo</i> distributions of TTPA <b>4</b>-<b>6</b> NPs are visually enriched in tumor sites and exhibited excellent PDT efficacy. This work demonstrates a novel strategy for AIE PDT and has the potential to play an essential role in clinical applications using nano-delivery systems.