Tumor Microenvironment-Triggered Dual-Prodrug Nanoplatform for Augmented Photodynamic Therapy: Self-Quenched Photosensitizer Activation and Nitric Oxide-Mediated Sensitization
- 1Hebei Key Laboratory of Functional Polymers, School of Chemical Engineering and Technology, Hebei University of Technology, Tianjin 300401, China
Abstract
Photodynamic therapy (PDT) holds great promise for cancer treatment owing to its spatiotemporal selectivity and minimal invasiveness. However, its therapeutic efficacy is hampered by photosensitizer self-quenching and intrinsic tumor hypoxia. Herein, we construct a tumor-microenvironment (TME)-activated dual-prodrug nanosystem (PheoA-CSSE-JSK) integrating the photosensitizer prodrug PheoA and nitric-oxide (NO) prodrug JSK for targeted tumor delivery. Tumor-abundant glutathione (GSH) cleaves disulfide bonds to restore the photoactivity of PheoA, which generates reactive oxygen species (ROS) under near-infrared irradiation. Meanwhile, intracellular GSH/glutathione S-transferase (GST) triggers NO release from JSK. NO-derived reactive nitrogen species (RNS) can degrade the tumor collagen matrix, which is inferred to potentially relieve hypoxia and further boost ROS production. GSH consumption, together with NO-mediated inhibition of the mitochondrial respiratory chain, may further augment ROS levels. We propose a self-reinforcing ROS-amplification working model involving PheoA photoactivation, potential NO-associated hypoxia alleviation, GSH depletion, and mitochondrial respiratory-chain inhibition. Collectively, these combined effects facilitate mitochondrial-dependent apoptosis and prominent antitumor outcomes. This TME-responsive dual-prodrug nanoplatform provides a promising strategy to augment PDT against hypoxic tumors.
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BibTeX
@article{gu2026tumor,
title = {{Tumor Microenvironment-Triggered Dual-Prodrug Nanoplatform for Augmented Photodynamic Therapy: Self-Quenched Photosensitizer Activation and Nitric Oxide-Mediated Sensitization}},
author = {Yuxuan Gu and Jiaqi Ding and Jialin Zhang and Xiaoxuan Liu and Zhuotao Xu and Jimin Zhang and Xiongwei Qu},
journal = {Polymers},
year = {2026},
month = oct,
doi = {10.3390/polym18202606},
url = {https://www.mdpi.com/2073-4360/18/20/2606},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Tumor Microenvironment-Triggered Dual-Prodrug Nanoplatform for Augmented Photodynamic Therapy: Self-Quenched Photosensitizer Activation and Nitric Oxide-Mediated Sensitization
AU - Yuxuan Gu
AU - Jiaqi Ding
AU - Jialin Zhang
AU - Xiaoxuan Liu
AU - Zhuotao Xu
AU - Jimin Zhang
AU - Xiongwei Qu
PY - 2026
DA - 2026/10/21
JO - Polymers
DO - 10.3390/polym18202606
UR - https://www.mdpi.com/2073-4360/18/20/2606
AB - Photodynamic therapy (PDT) holds great promise for cancer treatment owing to its spatiotemporal selectivity and minimal invasiveness. However, its therapeutic efficacy is hampered by photosensitizer self-quenching and intrinsic tumor hypoxia. Herein, we construct a tumor-microenvironment (TME)-activated dual-prodrug nanosystem (PheoA-CSSE-JSK) integrating the photosensitizer prodrug PheoA and nitric-oxide (NO) prodrug JSK for targeted tumor delivery. Tumor-abundant glutathione (GSH) cleaves disulfide bonds to restore the photoactivity of PheoA, which generates reactive oxygen species (ROS) under near-infrared irradiation. Meanwhile, intracellular GSH/glutathione S-transferase (GST) triggers NO release from JSK. NO-derived reactive nitrogen species (RNS) can degrade the tumor collagen matrix, which is inferred to potentially relieve hypoxia and further boost ROS production. GSH consumption, together with NO-mediated inhibition of the mitochondrial respiratory chain, may further augment ROS levels. We propose a self-reinforcing ROS-amplification working model involving PheoA photoactivation, potential NO-associated hypoxia alleviation, GSH depletion, and mitochondrial respiratory-chain inhibition. Collectively, these combined effects facilitate mitochondrial-dependent apoptosis and prominent antitumor outcomes. This TME-responsive dual-prodrug nanoplatform provides a promising strategy to augment PDT against hypoxic tumors.
SN - 2073-4360
ER -