Unlocking Phthalonitrile-Based Type I Photosensitizer Through D-A Modulation to Promote Electron Transfer

Type І photosensitizers (PSs) offer a promising strategy to overcome tumor hypoxia in photodynamic therapy (PDT) owing to their minimal oxygen dependence. However, their rational design remains elusive due to insufficient understanding of structure-property relationships. Herein, we leverage donor-π bridge-acceptor (D-π-A) conjugate modulation to design phthalonitrile-based Type І PSs through the systematic regulation of four critical parameters, including ΔE_ST, T₁ energy level, redox potential and steric hindrance, thereby optimizing efficient electron transfer pathway. These PSs exhibit aggregate-induced Type І reactive oxygen species (ROS) generation, driven by favorable intermolecular electronic interactions. Among them, DTPCH₃ demonstrates the highest Type І ROS production, attributed to its minimal ΔE_S1-T2 and the most effective intermolecular electron transfer interactions. Upon encapsulation with amphiphilic polymer F127, DTPCH₃ nanoparticles (DTPCH₃_NPs) retain efficient O₂ ^•- and HO• generation, resulting in potent cancer cell ablation and good hypoxic tolerance. In vivo studies further confirm significant tumor suppression by DTPCH₃_NPs. Overall, this work establishes a molecular design strategy for Type I PSs, opening new avenues for the development of next-generation PDT agents.