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Silver nanoparticles (AgNPs) are widely available as consumer goods, and over-the-counter or nutraceutical products used for alleged therapeutic and antibacterial properties. Among these products, AgNP topical therapy is proposed for treating patients with upper airway bacterial rhinosinusitis. While silver ion release from AgNPs in biological systems is well known, limited investigations actually characterize this silver ion release and their subsequent biological effects distinct from delivered particulate metallic silver. This is in part due to the analytical complexity and difficulty involved in distinguishing silver ion release from metallic AgNPs in biological media. Therefore, this study compared intranasal administration of AgNPs versus soluble silver ion (AgNO3) control to examine their transport and biological differences in tissues. First, we compared bactericidal activities of AgNPs and AgNO3 in those bacteria commonly associated with clinical rhinosinusitis in vitro. Next, we evaluated silver residence time in the sinus cavity after intranasal delivery of AgNPs and AgNO3 to mice, and characterized tissue distribution of silver in the sinonasal mucosal epithelium. We found that AgNPs show reduced bactericidal activity compared to AgNO3 (i.e., MBC of 15 ppm compared to 5 ppm), and significantly lower residence times in the sinus cavity (AgNP concentrations of 3.76 ppm after 3 h compared to 9 ppm for AgNO3). AgNPs were not readily taken up into or through respiratory epithelium, with very low silver levels found in blood and no detectable silver measured in the olfactory bulb and brain. Results indicate that limited tissue distribution of silver detected from AgNPs is due to AgNP dissolution to silver ion. AgNPs therefore demonstrate adequate safety through limited penetration and absorption, but limited potential therapeutic efficacy as antimicrobials in nasal applications, as concentrations of silver in the sinus cavity drop below the minimum bactericidal concentration within 3 h.