Synergistic Sulfur‐Atom Positioning and Acceptor Engineering Enable Preferential Type‐I Photodynamic Therapy

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ABSTRACT Less oxygen‐independent Type‐I reactive oxygen species (ROS) generated by photosensitizers offer distinct advantages for tumor photodynamic therapy (PDT). However, most conventional photosensitizers activate nonselective mixed ROS pathways, significantly hindering the advancement of PDT. In this study, we propose a synergistic molecular design strategy that integrates sulfur‐atom positioning and acceptor engineering to achieve preferential Type‐I ROS generation. We identified a novel near‐infrared Type‐I photosensitizer NS4 . Combined theoretical calculations and experimental characterizations demonstrate that sulfur substitution enhances the S 1 ‐T 1 intersystem crossing, while acceptor engineering promotes a pronounced twisted intramolecular charge transfer (TICT). This TICT effect lowers the energy of the S 1 state and stabilizes the T 1 state, thereby synergistically enabling the preferential production of Type‐I ROS. Both free NS4 derivative and NS‐NPs , self‐assembled from NS4 and F‐127, can generate substantial amounts of Type‐I ROS under 660 nm laser irradiation, effectively triggering tumor cell apoptosis. In vivo assessments confirm that a single dose of NS‐NPs significantly suppresses tumor growth with negligible systemic toxicity. This work establishes theoretical and structural guidelines for the rational design of high‐performance Type‐I photosensitizers and facilitates the further translation of PDT.