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.

化学动力学疗法 (CDT) 被公认为有效的活性氧 (ROS) 介导的抗癌策略。尤其是不稳定铁池（LIP）作为内源性亚铁催化剂的研究为未来CDT的发展铺平了道路。然而，有限的 H ₂ O ₂表达、温和的酸性、ROS 的还原型谷胱甘肽 (GSH) 消融等，都需要采用交替的过氧复合物来实现增强的 CDT 效果。作为非芬顿型底物，青蒿琥酯 (ART) 已被用作通过亚铁离子催化分解内过氧化物桥的自由基来源，然而，非肿瘤特异性递送、较差的药代动力学和疏水性最大限度地减少了自由基的产生。 ART 在生理系统中的功效。在此，我们通过将 ART 与 PEG 功能化的 Pd@Pt 纳米板 (PP NPs) 结合形成酯键来设计 PPA 纳米放大器，确保特定的肿瘤内酯酶响应性 ART 释放。值得注意的是，PPA 纳米放大器结合了Fe ²⁺对 ART 内过氧化物桥的原位分解超氧阴离子（O ₂ ^·-）和过氧化物酶（POD）样的内源性H ₂ O ₂酶催化PP 生成羟基自由基（·OH），从而实现放大的ROS 介导的肿瘤治疗。此外，PPA 显示出 GSH 破坏潜力，从而保护 ROS 免受 GSH 氧化的裂解。此外，PPA在近红外（NIR）区域的强吸收也赋予了PPA光声特性以实现成像引导的CDT。总之，PPA利用肿瘤部位高富集和酯酶反应性药物释放的优势，通过双重途径放大ROS信号，体外杀伤肿瘤细胞，体内抑制肿瘤生长。，从而实现高效的非芬顿CDT。我们相信我们基于 PPA 的新型抗肿瘤策略将拓宽 ROS 介导的肿瘤靶向治疗的未来。