Quercetin mitigates size-dependent oxidative and metabolic toxicity of citrate-coated silver nanoparticles in human erythrocytes

Silver nanoparticles (AgNP) are extensively used in consumer and medical products, making systemic exposure increasingly plausible. Once in circulation, AgNP directly interact with erythrocytes; however, AgNP effects on human erythrocytes remain poorly characterised, despite the central role of erythrocytes in maintaining blood homeostasis and the likelihood of direct nanoparticle contact following human exposure. Quercetin, a dietary flavonoid with potent antioxidant and anti-inflammatory activities, has shown cytoprotective potential against oxidative damage in various cell types, but its ability to counteract AgNP-induced erythrotoxicity has not yet been established. Accordingly, we (i) evaluated the effects of citrate-coated AgNP of 5, 10, and 50 nm on human erythrocytes and (ii) investigated the potential protective role of quercetin against AgNP-induced toxicity. The results showed that all citrate-coated AgNP induced haemolysis in human erythrocytes. Exposure to all three nanoparticle sizes markedly increased intracellular levels of pro-oxidant reactive species (RS). In particular, 10 and 50 nm AgNP caused a significant decrease in total glutathione (GSH) levels. Additionally, all tested AgNP also induced ATP decrease. Moreover, the 5 and 10 nm AgNP increased intracellular calcium levels. Remarkably, pre-treatment with quercetin conferred protection against almost all tested cytotoxic endpoints. However, quercetin failed to prevent total GSH loss and even exacerbated ATP depletion. Collectively, these findings provide the first integrated evidence of three sizes of AgNP-induced toxicity in human erythrocytes, demonstrating that quercetin confers broad, though not universal, protection. This underscores its potential as a modulator of nanoparticle-induced oxidative and metabolic damage.