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

ABSTRACT 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 Δ E ST , T 1 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, DTPCH 3 demonstrates the highest Type І ROS production, attributed to its minimal Δ E S1‐T2 and the most effective intermolecular electron transfer interactions. Upon encapsulation with amphiphilic polymer F127, DTPCH 3 nanoparticles (DTPCH 3 _NPs) retain efficient O 2 •− and HO• generation, resulting in potent cancer cell ablation and good hypoxic tolerance. In vivo studies further confirm significant tumor suppression by DTPCH 3 _NPs. Overall, this work establishes a molecular design strategy for Type I PSs, opening new avenues for the development of next‐generation PDT agents.