Lactic acid (LA) plays a major role in the occurrence, development, and spread of cancer. Enlightened by its high accumulation in tumor site, a novel lactate oxidase (LOD) conjugated two-dimensional Pd@Ir nanoplatform (Pd@Ir-LOD, PIL) was fabricated to combine cascade reaction with photothermal for tumor therapy. In detail, the overexpressed LA in tumor microenvironment (TME) was a key factor to activate the PIL-based cascade reaction: (1) Plenty of H₂O₂ could be generated from LA by the catalysis of LOD with O₂; (2) potent ·OH was produced from H₂O₂ due to the peroxidase (POD)-like activity of PIL; (3) meantime, PIL’s catalase (CAT)-like activity could decompose part H₂O₂ into O₂ to achieve the purpose of LA cyclic oxidization. Moreover, the reduced glutathione (GSH) scavenging capability of PIL might protect the produced reactive oxygen species (ROS) from being cleared to further improve the cascade therapeutic effect. More importantly, PIL had excellent photothermal conversion efficiency (37.35%) and manifested a surprising temperature rising effect in tumor. Taken together, the decreasing LA concentration, accumulation of high-toxic ROS, the depletion of GSH together with the higher intra-tumoral temperature potently enhanced in vivo antitumor therapy. Therefore, a promising therapeutic tactic based on PIL integrating endogenous LA consumption, chemodynamic therapy (CDT), and photothermal therapy (PTT) has been put forward.

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.