Route- and sex-dependent toxicity of clinical-stage silver nanoparticles in mice

Silver nanoparticles (AgNPs) are attractive therapeutic agents for highly specific applications; however, safety concerns about organ-specific toxicity following systemic exposure limit their development. Here, we present a multi-endpoint preclinical safety assessment of the clinical-stage silver nanomedicine Nowarta110 following repeated dermal topical, oral mucosal, and intravaginal administration in mice. The safety profile of Nowarta110 was evaluated through both longitudinal in-life monitoring and comprehensive terminal analyses, including hematology, serum biochemistry, urinalysis, organ weight measurements, detailed histopathological examination, and toxicokinetic profiling. Across all endpoints, no treatment-related toxicological effect was observed. Clinical pathology parameters, organ weights, and histopathological findings were consistent with controls, with no sex-dependent differences identified. Notably, plasma silver concentrations remained below the mass spectrometry limit of quantification at all time points, indicating no detectable systemic exposure. This lack of circulating silver supports the favorable safety profile of Nowarta110 across multiple local administration routes. Collectively, these findings further support the safety profile of this clinically-stage silver nanomedicine for local therapeutic applications.