Key Takeaways & Executive Findings
- •• • Guanidinium modification converts non-photosensitizing fluorophores into ROS generators with prolonged triplet lifetimes and considerable ROS production, as evidenced by EPR and HRMS identification of stable radical cations. • • The strategy is general, not limited to specific molecular structures, enabling broad applicability across diverse fluorophore scaffolds. • • In vitro and in vivo experiments demonstrate that guanidinium-modified photosensitizers induce immunogenic cell death (ICD) and elicit potent anti-tumor immunity, achieving significant tumor regression. • • Mechanistic studies reveal that nitrogen-centered radical cations stabilized by p-π conjugation enhance ISC and prolong triplet excited state lifetimes, providing a new design principle for heavy-atom-free photosensitizers.
Abstract
Designing photosensitizers with efficient intersystem crossing (ISC) and long-lived triplet excited states is critical for photodynamic therapy (PDT). However, conventional molecular design principles often rely on heavy-atom effects or specific donor-acceptor architectures, limiting generality. Here, we report a facile and rational strategy to convert intrinsically non-photosensitizing fluorophores into effective reactive oxygen species (ROS) generators by introducing guanidinium substituents. The modified photosensitizers exhibit prolonged triplet excited state lifetimes and considerable ROS production, in stark contrast to unmodified fluorophores which show intense fluorescence and negligible ROS generation. Electron paramagnetic resonance spectroscopy and high-resolution mass spectrometry confirm the formation of stable nitrogen-centered radical cations on the guanidinium moiety, stabilized by p-π conjugation. Mechanistic studies indicate that these radicals promote ISC and prolong triplet state lifetimes. In vitro and in vivo experiments demonstrate that guanidinium-modified photosensitizers induce immunogenic cell death (ICD) and elicit potent anti-tumor immunity. This work provides a universal and facile strategy for designing organic photosensitizers through stable radical cation-containing building blocks, expanding the scope of PDT agents.
1. Introduction
Photodynamic therapy (PDT) relies on photosensitizers that generate reactive oxygen species (ROS) upon light irradiation, yet many organic fluorophores exhibit strong fluorescence and negligible ROS production due to inefficient intersystem crossing (ISC). Conventional strategies to enhance ISC often employ heavy atoms or elaborate donor-acceptor architectures, which can introduce toxicity or synthetic complexity. The bottleneck remains the rational design of heavy-atom-free photosensitizers with high triplet yields and long-lived excited states, particularly for biomedical applications where biocompatibility and tumor penetration are paramount.
This work addresses this challenge by introducing guanidinium substituents onto non-photosensitizing fluorophores, which spontaneously form stable radical cations that promote ISC via a radical-pair mechanism. This approach is universal, as it does not depend on specific molecular scaffolds, and it significantly enhances ROS generation while maintaining biocompatibility. The resulting photosensitizers demonstrate potent anti-tumor efficacy through immunogenic cell death, offering a new paradigm for designing effective PDT agents.
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HE Wenjing, CAI Zhipeng, GAO Ji, ZHANG Xianming, WANG Fangliang, WEI Zhuocai, WEI Fangfang, WEI Luyao, LYU Xingyu, ZHOU Li, LI Kai (2026). Transforming Non-Photosensitizing Fluorophores into ROS Photogenerators via Radical-Promoted Intersystem Crossing. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3653-2
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Frequently Asked Questions
What is the mechanism by which guanidinium modification enhances intersystem crossing?
Guanidinium substituents form stable nitrogen-centered radical cations, stabilized by p-π conjugation. These radicals promote ISC via a radical-pair mechanism, increasing the triplet excited state lifetime and enabling efficient ROS generation.
How does the strategy demonstrate generality across different fluorophores?
The design principle is not limited to specific molecular structures; it was successfully applied to multiple fluorophore scaffolds, indicating that guanidinium modification can be universally adopted to convert non-photosensitizing dyes into effective photosensitizers.
What evidence supports the formation of stable radicals?
Electron paramagnetic resonance (EPR) spectroscopy and high-resolution mass spectrometry (HRMS) confirmed the presence of stable radical cations on the guanidinium moiety, which are pivotal for the enhanced ISC.
What are the in vivo anti-tumor effects of the guanidinium-modified photosensitizers?
In vivo experiments demonstrated that these photosensitizers induce immunogenic cell death (ICD), leading to potent anti-tumor immunity and significant tumor regression, as evidenced by reduced tumor volumes and increased survival rates.
What are the potential limitations or challenges for clinical translation?
While the strategy shows promise, further optimization of photophysical properties (e.g., absorption wavelength) and biocompatibility is needed. Additionally, long-term stability and pharmacokinetics must be evaluated in preclinical models before clinical application.
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