Although nanodrugs based on antiangiogenic and oxidative stress have received widespread attention in oncotherapy, low delivery efficiency and drug payload have greatly hindered their further applications. The self-targeting carrier-free metal-organic nanodrugs are constructed via the dynamic ligand-driven self-assembly of anti-angiogenesis pseudolaric acid B (PAB), Fenton-like agent copper ion, and the chemo-drug pemetrexed (PEM) to enhance anti-angiogenic-oxidative stress oncotherapy. After intravenous injection, it is found that such nanodrugs can be efficiently accumulated in tumor site and internalized into tumor cells by folate receptors-mediated self-targeting. After that, nanodrugs are disassembled to achieve the burst release of drugs under stimuli of acidic lysosome and endogenous glutathione (GSH). Interestingly, the released Cu^[II] can efficiently decompose the endogenous hydrogen peroxide (H₂O₂) into hydroxyl radicals (·OH) and significantly weaken reactive oxygen species (ROS) elimination by downregulating endogenous GSH to self-amplify intracellular oxidative stress. Meanwhile, the released PAB can obviously inhibit the secretion of vascular endothelial growth factor (VEGF), block the formation of new blood vessels, and regulate the conformation of VEGF receptor 2 (VEGFR2) to inhibit the angiogenesis signaling pathway. After two weeks of treatment, PEM-Cu^[II]-PAB (PCP) nanodrugs achieved a 95% tumor inhibition rate and 100% survival rate in tumor-bearing mice. Taken together, our study can expect to provide a promising method for targeted oncotherapy based on the synergistic therapy of antiangiogenic or oxidative stress.

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.