A nucleus-targeting type-I photosensitive nanoplatform for DNA-binding-enhanced photodynamic therapy

Photodynamic therapy (PDT), as a promising anticancer strategy, has attracted much attention due to the advantages of non-invasiveness, temporal-spatial selectivity, and low tendency to induce drug resistance. However, the clinical translation of PDT faces severe challenges, owing to the oxygen-demanding nature of ROS generation and the ultrashort lifespan and narrow diffusion radius of ROS. Herein, we report a nanoplatform that integrates a tumor microenvironment (TME)-responsive polymeric vehicle with an aggregation-induced emission (AIE) type-I photosensitizer (TD) with nucleus-targeting and DNA-binding abilities. This nanoplatform enables specific delivery in the acidic and GSH-overexpressed TME via pH/redox dual responsiveness, ensuring selective accumulation and low off-target effects. By mimicking the nucleus-targeting chemical structure of Hoechst, TD can penetrate the nuclear envelope, intercalate DNA, and generate hydroxyl radicals and superoxide anion radicals near genetic materials, causing DNA damage and apoptosis even under hypoxia. In vitro and in vivo studies confirmed the effective ROS generation, antitumor efficacy, and good biocompatibility of the nanoplatform. The DNA-binding-enhanced PDT strategy provides a promising pathway for precision phototherapeutics.