Abstract <p>The incidence of invasive fungal infections is rising steadily, driven by the expanding immunocompromised patient population and the limited availability of effective antifungal interventions. Among medically important fungi, airborne <i>Aspergillus</i> conidia are especially relevant to environmental quality control because they can disseminate through air and contaminate healthcare settings. Here, we designed and synthesized a novel ultrafine sodium chloride powder (nanosalt) by anti-solvent precipitation coupled with high-energy nanonization and evaluated its in vitro antifungal activity in a controlled spray co-exposure system using <i>Aspergillus</i> spp. as the primary airborne fungal species. In addition, <i>Candida albicans</i> and <i>Cryptococcus neoformans</i> were also to be tested for the antifungal broad-spectrum by this system even though they do not belong to typical hospital airborne transmission. Nanosalt showed marked fungicidal activity against the tested human fungal pathogens. Further morphological observations in nanosalt-treated <i>A. fumigatus</i> conidia indicated severe cell wall and membrane damage, pore-like structural disruption, leakage-associated loss of integrity accompanied with a time-dependent increase of fungal intracellular reactive oxygen species. Findings in this study mainly identify nanosalt not only might be efficient anti-airborne fungal pathogens but also could be a potential broad-spectrum antifungal reagents. Although currently used aerosol chamber model still has limitation compared actual clinical environment, future practical air-disinfection applications in clinics and related biosafety evaluations are still required.</p> Key points <p>• <i>Novel nanosalt particles were generated by anti-solvent precipitation coupled with high-energy nanonization.</i></p> <p>• <i>Nanosalts exhibit broad fungicidal activity by disrupting fungal cell walls and membranes.</i></p> <p>• <i>Nanosalt is a candidate for dry environmental antifungal disinfectant.</i></p>