Tumor Microenvironment-Triggered Dual-Prodrug Nanoplatform for Augmented Photodynamic Therapy: Self-Quenched Photosensitizer Activation and Nitric Oxide-Mediated Sensitization

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.