Systemic administration of drugs is ineffective in the treatment of central nervous system disorders because of the blood-brain barrier. Nasal administration has been suggested as an alternative administration route as drugs absorbed in the olfactory epithelium bypass the blood-brain barrier and reach the brain within minutes. However, the nasal mucosa properties (e.g., tonicity, pH) are not constant because of physiological and environmental factors, and this might limit the therapeutic outcome of nanocarrier-based formulations. To shine light on the impact of environmental ionic strength on nanocarrier-based formulations, we have studied how liposomal formulations respond to the change of tonicity of the external environment. Large unilamellar vesicles loaded with 6 different drugs were exposed to different hypotonic environments, creating an osmotic gradient within the inner core and external environment of the liposomes up to 650 mOsm/kg. Both size and polydispersity of liposomes were significantly affected by tonicity changes. Moreover, the release kinetics of hydrophilic and lipophilic drugs were largely enhanced by hypotonic environments. These results clearly demonstrate that the environmental ionic strength has an impact on liposomal formulation stability and drug release kinetics and it should be considered when liposomal formulations for nose-to-brain targeted drug delivery are designed.