Endogenous Fe²⁺-activated ROS nanoamplifier for esterase- responsive and photoacoustic imaging-monitored therapeutic improvement

Chemodynamic therapy (CDT) is well acknowledged as potent reactive oxygen species (ROS)-mediated anticancer strategy. Especially, the study about labile iron pool (LIP) as endogenous ferrous catalyzer has paved the way for future CDT development. However, limited H₂O₂ expression, mild acidity, reduced glutathione (GSH) ablation of ROS, etc., all require employing alternate peroxo-complex to achieve enhanced CDT effect. As a non-Fenton-type substrate, artesunate (ART) has been utilized as a source of free radicals through decomposition of endoperoxide bridges catalyzed by ferrous ions, nonetheless, the non-tumor-specific delivery, inferior pharmacokinetics, and hydrophobic nature minimize the efficacy of ART in physiological systems. Herein, we devise a PPA nanoamplifier by conjugating ART with PEG-functionalized Pd@Pt nanoplates (PP NPs) to form ester linkage, ensuring specific intratumoral esterase-responsive ART release. Significantly, the PPA nanoamplifier combines the in situ decomposition of ART's endoperoxide bridges by Fe²⁺ to superoxide anions (O₂^·-) and peroxidase (POD)-like enzymatic catalysis of endogenous H₂O₂ by PP to hydroxyl radicals (·OH), thus achieving amplified ROS-mediated tumor therapy. Besides, PPA displays GSH destruction potential, thereby protecting ROS from the cleavage by GSH oxidation. In addition, the strong absorption of PPA in near-infrared (NIR) region also endows PPA with photoacoustic property to realize imaging-guided CDT. In short, by taking advantages of the high enrichment and esterase- responsive drug release at tumor sites, PPA amplified ROS signals via dual pathways, killing tumor cells in vitro and inhibiting tumor growth in vivo, thereby realizing high-efficiency non-Fenton CDT. We believe our novel anti-tumor strategy based on PPA will broaden the future of ROS-mediated tumor-targeted therapy.