A Hydrophilicity‐Switchable, Self‐Immobilizing Near‐Infrared Photosensitizer for γ‐Glutamyltransferase‐Activated Precision Photodynamic Therapy

ABSTRACT Photodynamic therapy (PDT) is a minimally invasive cancer treatment, but its clinical translation is limited by the intrinsic conflict between hydrophilicity for systemic delivery and hydrophobicity for cellular uptake and retention. Here, we report a γ‐glutamyltransferase (GGT)‐activatable, hydrophilicity‐switchable, and self‐immobilizing near‐infrared photosensitizer, GGT‐PS2 . Initially hydrophilic and photoinactive, GGT‐PS2 undergoes enzymatic cleavage by tumor‐associated GGT, triggering a hydrophilic‐to‐hydrophobic transition and generating a reactive quinone methide intermediate for covalent immobilization. This process simultaneously activates near‐infrared fluorescence and singlet oxygen production. In vitro studies demonstrate GGT‐specific activation, efficient protein binding, and enhanced photodynamic performance compared to control analogs. In a HeLa tumor xenograft model, GGT‐PS2 achieves selective tumor accumulation and prolonged retention, resulting in complete tumor regression after a single intravenous administration with light irradiation, without observable toxicity or recurrence. This “one‐to‐multi” design provides an effective strategy to overcome the solubility–retention trade‐off, offering a promising platform for precision PDT.