Substrate-free generation of photosensitizer radical-ion pairs for photoredox therapy

Photodynamic therapy (PDT) is a promising clinical treatment modality, yet its efficacy remains limited by inefficient photon-to-ROS conversion and severe oxygen dependence. Photogenerated radical-ion (PS⁺•/PS⁻•) pairs are particularly attractive because they broaden photoredox pathways for hypoxia-tolerant ROS production. However, conventional substrate-dependent mechanism typically generates only one radical species, limiting both photoredox diversity and overall ROS production. Therefore, developing single-component photosensitizer systems that efficiently generate PS⁺•/PS⁻• pairs without external substrates is crucial for expanding photoredox mechanisms and overcoming hypoxia-limited PDT.

 

In a new paper published in Light: Science & Applications, a team of scientists led by Professor Wei Huang from the State Key Laboratory of Flexible Electronics (LoFE), Frontiers Science Center for Flexible Electronics, Institute of Flexible Electronics (IFE), Northwestern Polytechnical University, have developed a substrate-free mechanism for generating long-lived PS⁺•/PS⁻• pairs via noncovalent homodimer fission. This mechanism efficiently generates photosensitizer radical ion pairs (PS⁺•/PS⁻•) without external substrates, unlocking multiple photoredox pathways. By integrating in situ oxygen generation, oxygen reduction, and sustained reactive oxygen species (ROS) production, this strategy establishes a self-oxygen-supplying cycle for highly effective hypoxia-tolerant photodynamic therapy, offering a new paradigm to overcome the hypoxia-induced limitations of conventional PDT.

 

The new mechanism is centered around noncovalent photosensitizer homodimer fission. Upon light irradiation, the noncovalent homodimer undergoes fission to generate long-lived PS⁺•/PS⁻• radical-ion pairs. Unlike conventional photoredox systems that usually rely on external electron donors or acceptors and often produce only one type of radical species, this single-component system simultaneously generates both oxidative and reductive photosensitizer radicals. As a result, PS⁺• can oxidize water to produce oxygen in situ, while PS⁻• can reduce oxygen to generate superoxide anions and hydroxyl radicals, thereby forming a self-oxygen-supplying ROS generation cycle.

 

These scientists summarize the operational principle of their mechanism:

“We demonstrate a substrate-free mechanism for generating long-lived PS⁺•/PS⁻• pairs through noncovalent homodimer fission, enabling hypoxia-tolerant ROS production. Multiple spectroscopic techniques provide direct experimental evidence for homodimer formation, fission, and subsequent generation of substantial PS⁺•/PS⁻• pairs. The resulting PS⁺• oxidizes water to generate oxygen in situ, which is further reduced by PS⁻• to produce hydroxyl radicals and superoxide anions, thereby establishing a self-oxygen-supplying ROS generation cycle.”

 

Based on this mechanism, the photosensitizer exhibits markedly enhanced ROS generation compared with a commercial photosensitizer. It achieves a 2.3-fold increase in superoxide anion generation and a 4.9-fold increase in hydroxyl radical generation, leading to a 7.9-fold enhancement in antibacterial activity and a 2.2-fold acceleration of epithelialization in wound models.

 

“First, this work identifies a distinct light-driven mechanism for substrate-free radical-ion-pair generation, providing important mechanistic insight into PDT while reducing system complexity and improving reproducibility for clinical translation. Second, it establishes a rigorous multidisciplinary framework for radical characterization, which should be broadly useful for identifying short-lived radicals in various light-driven systems,” the scientists forecast.

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