Excited-State-Guided Molecular Design System for Type I Photosensitizers

Type I photosensitizers (PSs), which generate Type I reactive oxygen species (ROS) through the electron transfer pathway and remain effective under hypoxic conditions, provide a promising solution to overcome the oxygen dependence of the currently dominant Type II PSs in photodynamic therapy (PDT). Yet, the lack of a mechanistic framework for designing Type I PSs has made their discovery largely empirical. Here, we present an excited-state-guided molecular design system that treats key excited-state properties, low first triplet-state (T 1 ) energy, and a small singlet–triplet (Δ E ST ) energy gap as joint optimization objectives to suggest candidates with Type I characteristics. Starting from 147 molecular fragments, the system generates 713 candidate molecules designed for Type I behavior. Two representative molecules (NIDPP and NAAID) are further synthesized and experimentally validated, both exhibiting robust superoxide anion (O 2 •– ) radical production, thereby confirming Type I behavior. This study demonstrates that the excited-state-guided molecular design strategy is effective toward the discovery of next-generation PSs for hypoxia-resilient PDT.