Immunometabolic signatures induced by silver sulfide nanoparticles in freshwater clams

Aquatic ecosystems are increasingly at risk of exposure to silver sulfide nanoparticles (Ag₂S NPs) through anthropogenic waste streams, with these particles traditionally considered less toxic due to their low solubility. However, emerging evidence suggests that the oxidative dissolution of Ag₂S NPs can lead to the release of silver ions (Ag⁺), raising questions about whether Ag₂S NP-induced toxicity can be explained by Ag⁺ release in aquatic environments. Herein, we assess the immunotoxicity of Ag₂S NPs and Ag⁺ in freshwater clams (Corbicula fluminea) through an immunometabolic framework. Environmental concentrations of Ag₂S NPs caused substantial inflammation, broad activation of the innate immune system, and a pronounced oxidative burst, while Ag⁺ at equivalent silver mass mainly caused cytotoxic and did not induce immune activation. Metabolomic and transcriptomic profiling revealed distinct features of Ag₂S NPs compared with Ag⁺, characterized by tissue-level glucose metabolic responses involving PPP-related features and upregulated proinflammatory signaling genes. These findings provide an immunometabolic perspective for understanding the Ag₂S NP-induced toxicity, suggesting that the observed toxicity cannot be fully explained by Ag⁺ release during aqueous exposure and highlighting the potential ecological risk of metal sulfide nanoparticles to benthic communities. Our results suggest that Ag₂S NPs pose a greater environmental hazard than previously thought, warranting further consideration in nanoparticle risk assessments.