ROS-catalytic self-amplifying benzothiophenazine-based photosensitive conjugates for photodynamic-immuno therapy

Activatable photosensitizer (aPS)-mediated photodynamic therapy (PDT) holds great potential towards precision cancer treatment, but which generally suffers from low therapeutic outcomes due to the low activation efficiency of aPS and the low phototherapeutic effect of single PDT. In this study, we present a newly aPS designing strategy based on benzothiophenazine (BP) for fabrication of the robust small-molecule photosensitizer conjugates (SMPCs). Specifically, after systematically studying the photosensitizing mechanism of BP, a fully caged pro-photosensitizing platform (BP-Cl) was established, based on which we can introduced various amine molecules to create a series of reactive oxygen species (ROS)-catalytic self-amplifying SMPCs. As a proof of concept, we synthesized a SMPC (BP-Mel) by employing the chemotherapeutic melphalan to BP-Cl. Upon triggered by endogenous ROS, BP-Mel can achieve self-amplified activation under infrared illumination to efficiently produce the active BP for type I PDT, and along with the release of melphalan to induce immunogenic cell death in breast cancer cells. BP-Mel was encapsulated with resiquimod (R848) to form the nanoagonist (BMR), where BP-Mel induces localized tumor damage and immunogenic cell death and the TLR7/8 agonist R848 potently stimulates dendritic cell maturation and enhances tumor-specific T cell responses. BMR-mediated combination therapy induces powerful tumor suppression and immunotherapeutic cascade in EMT6-tumor-bearing mice. This study presents a scalable strategy for the customization of activatable photosensitive conjugates, exemplifying precise and efficient PDT.