Laboratory investigations of aerosol physico-chemical properties are usually initiated by spray-drying processes. Morphology of the generated particles may vary largely under different spray-drying conditions, which may further affect the characterization of particle properties. However, only limited data is available on the morphology of nebulized submicron particles, particularly for protein particles. To fill this gap, a centrifugal particle mass analyzer coupled with a scanning mobility particle sizer was used to analyze the effective density, an indicator of particle morphology, of nebulized protein particles (bovine serum albumin and ovalbumin) in a size range from 40 to 200 nm. Results indicate that the effective density of the protein particles generated via spray-drying processes is mainly determined by the competition between the removal of liquid water and the redistribution of the solute monomers in the sprayed droplets. Factors increasing the time needed for solute monomers redistribution (e.g. lower solution concentration and larger particle dry size) or decreasing the time needed for liquid water removal (e.g. higher drying rate) may result in a lower particle effective density, meaning a semi-solid structure or partially hollow morphology. This is also confirmed by the particle hygroscopicity measured with a nano-particle hygroscopic tandem differential mobility analyzer and a high humidity tandem differential mobility analyzer. Our results suggest that the factors affecting the morphology of particles may be complex and coupled with each other, highlighting the importance of monitoring particle effective densities in studies using aerosol particles generated via spray-drying processes.