Silver Nanoparticles Specially Amplify the Anticancer Effects of Platinum-Based Drugs by Disrupting Cellular Nucleotide and Sulfur Homeostasis

Numerous nanoparticles (NPs) have emerged as promising physical vehicles to deliver drugs for cancer treatment, yet the effect of their biochemical activities on drug efficacy is rarely considered. Here, we demonstrate that silver nanoparticles (AgNPs) specially potentiate the anticancer efficacy of platinum-based drugs, increasing apoptosis rates by up to 5.26-fold across multiple cancer cell lines. Untargeted metabolomics identified the AgNPs-induced downregulation of 3'-phosphoadenosine 5'-phosphosulfate (PAPS) and glutathione, key components of sulfur metabolism, alongside depletion of nucleotide pools critical for DNA repair. The dual action─reducing thiol-containing molecules to decrease drug inactivation while reducing nucleotide to inhibit DNA repair─led to elevated Pt-DNA adducts and exacerbated DNA damage. <i>In vivo</i>, AgNPs-cisplatin cotreatment suppressed tumor growth compared to cisplatin alone, accompanied by reduced thiol level and increased platinum accumulation in the tumor. Our findings highlight that the match of nanoparticle and drug in their biochemical activities will maximize the therapeutic efficacy for cancer.