Side-Chain Sulfonation to Modulate Hydroxyl Radical Generators for Efficient Suppression of Hepatoma Cells under Hypoxia

The development of type I photosensitizer (PS) targeting subcellular organelles that directly destroy key subcellular compartments and overcome the hypoxic environment has become a critical breakthrough for improving therapeutic effects on tumors. Herein, we proposed a simple tactic of side-chain sulfonation to construct the subcellular organelles targeting type I PS. Initially, the traditional lipophilic donor-π-acceptor (D-π-A) system (3SSYDI) was constructed, which exhibited type II reactive oxygen species generation capability and lipid droplets (LDs)-targeting property. Innovatively, the heavy-atom-free sulfonate ion was introduced to achieve side-chain sulfonation. The modulated 3SSYDS not only exhibited optimal biosafety but also possessed lower impedance and higher photocurrent intensity, which facilitated superior electron transfer to generate superoxide anions (O₂^-•). Notably, in biological aqueous systems, O₂^-• combined with protons to further produce hydrogen peroxide, thereby triggering the Haber-Weiss reaction to produce the most reactive hydroxyl radical (•OH), achieving more effective suppression of cancer cells even under hypoxic conditions. This study presents a simple strategy of side-chain sulfonation that activated highly toxic •OH generation in traditional D-π-A systems, providing an efficient solution for treating hypoxic tumors.