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<p>Photodynamic therapy using an appropriate photocatalyst results in the production of cytotoxic reactive oxygen species for tumor ablation. However, the inherent O<sub>2</sub> dependence of conventional photodynamic therapy limits its clinical translation. To overcome this challenge, here we developed a selenium-substituted Nile blue derivative (ENBSe) as a versatile O<sub>2</sub>-independent photocatalyst. Under near-infrared light irradiation, ENBSe can drive the biological oxidation of NADH to NAD<sup>+</sup> while simultaneously triggering the cascade reduction of cytochrome <i>c</i> (Fe³⁺ to Fe²⁺), even in the absence of O<sub>2</sub>. To improve tumor specificity and targeting, we further developed a conditionally activatable photoredox catalysis (ConAPC) system. ENBSe is covalently attached to 4-nitrobenzyl chloride via a carbonic anhydride bond, wherein the nitro group can be specifically cleaved by nitroreductase (NTR), an enzyme overexpressed in hypoxic tissues. Such ConAPC design prevents reaction with NADH and quenches the fluorescences of ENBSe, which means that the drug molecule, ENBSe–NTR, is catalytically inactive. ENBSe–NTR is, to our knowledge, the first tumor microenvironment-responsive ConAPC molecule that enables O<sub>2</sub>-free, tumor-specific catalytic therapy. By replacing the 4-nitrobenzyl chloride group, it might be possible to target cells with different microenvironmental conditions. This protocol presents a standardized workflow encompassing the synthesis of ENBSe and its application for photocatalytic modulation of cellular electron flow in the mitochondrial electron transport chain via an O<sub>2</sub>-independent mechanism of action. The outlined protocol specifies a synthesis period of ~4 d for ENBSe, ~4 h for photoredox spectroscopic characterization and 4–5 weeks for photodiagnostic assessment in cancer cell and mice models.</p>

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Preparation of ENBSe-based photoredox catalysts for O2-independent phototherapy in living systems

  • 期刊论文

  • 发表日期：

    2026年3月16日

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  • Yingying Zhang,
  • Yingnan Wu,
  • Zehao Jing,
  • Xiaoqiang Chen,
  • Mingle Li,
  • Xiaojun Peng

摘要

Photodynamic therapy using an appropriate photocatalyst results in the production of cytotoxic reactive oxygen species for tumor ablation. However, the inherent O2 dependence of conventional photodynamic therapy limits its clinical translation. To overcome this challenge, here we developed a selenium-substituted Nile blue derivative (ENBSe) as a versatile O2-independent photocatalyst. Under near-infrared light irradiation, ENBSe can drive the biological oxidation of NADH to NAD+ while simultaneously triggering the cascade reduction of cytochrome c (Fe³⁺ to Fe²⁺), even in the absence of O2. To improve tumor specificity and targeting, we further developed a conditionally activatable photoredox catalysis (ConAPC) system. ENBSe is covalently attached to 4-nitrobenzyl chloride via a carbonic anhydride bond, wherein the nitro group can be specifically cleaved by nitroreductase (NTR), an enzyme overexpressed in hypoxic tissues. Such ConAPC design prevents reaction with NADH and quenches the fluorescences of ENBSe, which means that the drug molecule, ENBSe–NTR, is catalytically inactive. ENBSe–NTR is, to our knowledge, the first tumor microenvironment-responsive ConAPC molecule that enables O2-free, tumor-specific catalytic therapy. By replacing the 4-nitrobenzyl chloride group, it might be possible to target cells with different microenvironmental conditions. This protocol presents a standardized workflow encompassing the synthesis of ENBSe and its application for photocatalytic modulation of cellular electron flow in the mitochondrial electron transport chain via an O2-independent mechanism of action. The outlined protocol specifies a synthesis period of ~4 d for ENBSe, ~4 h for photoredox spectroscopic characterization and 4–5 weeks for photodiagnostic assessment in cancer cell and mice models.